U.S. patent application number 12/291753 was filed with the patent office on 2010-05-13 for substituted pyrano [2,3-b] pyridinamine compounds as beta-secretase modulators and methods of use.
This patent application is currently assigned to Amgen Inc.. Invention is credited to Russell Graceffa, Matthew Kaller, Daniel La, Patricia Lopez, Vinod F. Patel, Wenge Zhong.
Application Number | 20100120774 12/291753 |
Document ID | / |
Family ID | 42165799 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100120774 |
Kind Code |
A1 |
Graceffa; Russell ; et
al. |
May 13, 2010 |
Substituted Pyrano [2,3-b] Pyridinamine compounds as beta-secretase
modulators and methods of use
Abstract
The present invention comprises a new class of compounds useful
for the modulation of Beta-secretase enzyme activity and for the
treatment of Beta-secretase mediated diseases, including
Alzheimer's disease (AD) and related conditions. In one embodiment,
the compounds have a general Formula I ##STR00001## wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, A.sup.1, A.sup.2,
A.sup.3, A.sup.4, X and Z are defined herein. The invention also
includes use of these compounds in pharmaceutical compositions for
treatment, prophylactic or therapeutic, of disorders and conditions
related to the activity of beta-secretase protein. Such disorders
include, for example, Alzheimer's Disease (AD), cognitive deficits
and impairment, schizophrenia and other similar central nervous
system conditions. The invention also comprises further embodiments
of Formula II, intermediates and processes useful for the
preparation of compounds of Formulas I and II.
Inventors: |
Graceffa; Russell; (Hampton,
NH) ; Kaller; Matthew; (Ventura, CA) ; La;
Daniel; (Brookline, MA) ; Lopez; Patricia;
(West Hills, CA) ; Patel; Vinod F.; (Acton,
MA) ; Zhong; Wenge; (Thousand Oaks, CA) |
Correspondence
Address: |
AMGEN INC.
MAIL STOP 28-2-C, ONE AMGEN CENTER DRIVE
THOUSAND OAKS
CA
91320-1799
US
|
Assignee: |
Amgen Inc.
Thousand Oaks
CA
|
Family ID: |
42165799 |
Appl. No.: |
12/291753 |
Filed: |
November 12, 2008 |
Current U.S.
Class: |
514/249 ;
514/275; 544/350; 546/15 |
Current CPC
Class: |
A61P 25/16 20180101;
C07D 519/00 20130101; A61P 25/28 20180101; C07D 417/12 20130101;
C07D 487/04 20130101; C07D 405/12 20130101; C07D 311/96 20130101;
C07D 491/052 20130101; C07D 413/12 20130101 |
Class at
Publication: |
514/249 ;
544/350; 514/275; 546/15 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; C07D 487/04 20060101 C07D487/04; A61K 31/506 20060101
A61K031/506; C07D 405/12 20060101 C07D405/12; A61P 25/28 20060101
A61P025/28 |
Claims
1. A compound of Formula I: ##STR00050## or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.1 is a
partially or fully unsaturated 4-8 membered monocyclic or 6-12
membered bicyclic ring, said ring formed of carbon atoms optionally
including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said heteroatoms selected from O, N, or S, and wherein
said ring is optionally substituted independently with one or more
substituents of oxo, R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7,
C(O)R.sup.7, OC(O)R.sup.7, COOR.sup.7,
C(O)NR.sup.7R.sup.7NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7;
R.sup.2 is a partially or fully saturated or fully unsaturated 3-8
membered monocyclic or 6-12 membered bicyclic ring, said ring
formed of carbon atoms optionally including 1-3 heteroatoms if
monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms
selected from O, N, or S, and wherein said ring is optionally
substituted independently with one or more substituents of oxo,
R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7, C(O)R.sup.7,
OC(O)R.sup.7, COOR.sup.7, C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7;
each R.sup.3, independently, is H, haloalkyl, CN, C.sub.1-6-alkyl,
C.sub.2-8-alkenyl, C.sub.2-8-alkynyl, C.sub.3-8-cycloalkyl or
C.sub.4-8-cycloalkenyl, each of the C.sub.1-6-alkyl,
C.sub.2-8-alkenyl, C.sub.2-8-alkynyl, C.sub.3-8-cycloalkyl and
C.sub.4-8-cycloalkenyl optionally comprising 1-2 heteroatoms
selected from N, O and S and optionally substituted with 1-5
substituents of R.sup.7; R.sup.4 is H, halo or C.sub.1-6-alkyl;
R.sup.5 is H, halo, haloalkyl, oxo, C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH or NH.sub.2, wherein the
C.sub.1-6-alkyl and the C.sub.1-6-alkyl portion of
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl
and --N-di-C.sub.1-6-alkyl are optionally substituted independently
with 1-5 substituents of R.sup.7; each of A.sup.1, A.sup.2, A.sup.3
and A.sup.4, independently, is N, CH or CR.sup.6, provided that no
more than two of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 is N; X is
CHR.sup.6, CR.sup.6R.sup.6, C(.dbd.O), O, NR.sup.6, or S(O).sub.o
wherein o is 0, 1 or 2; Z is a 3-6 membered spirocyclic ring formed
of carbon atoms optionally including 1-3 heteroatoms selected from
O, N and S and optionally substituted independently with 1-3
substituents of R.sup.7; each R.sup.6, independently, is halo,
haloalkyl, C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH, NH.sub.2, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl, or C.sub.4-8-cycloalkenyl,
wherein the C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl and the
C.sub.1-6-alkyl portion of --O--C.sub.1-6-alkyl,
--S--C.sub.1-6alkyl, --NH --C.sub.1-6-alkyl and
--N-di-C.sub.1-6-alkyl are optionally substituted with 1-5
substituents of R.sup.7; or R.sup.6 is a fully unsaturated or
partially or fully unsaturated 5- or 6-membered monocyclic or
bicyclic ring formed of carbon atoms, said ring optionally
including 1-5 heteroatoms selected from O, N, or S and optionally
substituted with one or more substituents of R.sup.7; and each
R.sup.7, independently, is H, halo, haloalkyl, CN, OH, NO.sub.2,
NH.sub.2, acetyl, oxo, C.sub.1-10-alkyl, C.sub.2-10-alkenyl,
C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl or a fully saturated or
partially or fully unsaturated 3-8 membered monocyclic or a 6-12
membered bicyclic ring, said ring formed of carbon atoms optionally
including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said heteroatoms selected from O, N, or S, wherein each
of the C.sub.1-10-alkyl, C.sub.2-10-alkenyl, C.sub.2-10-alkynyl,
C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl and ring is optionally
substituted independently with 1-5 substituents of halo, haloalkyl,
CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,
propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl,
hexyl, cyclohexyl, C.sub.1-10-alkylamino-,
C.sub.1-10-dialkylamino-, C.sub.1-10-thioalkoxyl, benzyl or
phenyl.
2. The compound of claim 1 wherein R.sup.1 is an optionally
substituted ring selected from phenyl, naphthyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, thienopyrimidinyl, thienopyridinyl, furyl, pyrrolyl,
pyrazolyl, pyrazolopyridinyl, pyrazoliopyrimidinyl, imidazolyl,
triazolyl, triazolopyrazinyl, triazolopyridinyl, tetrazolyl,
thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl,
oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl and
benzodioxolyl.
3. The compound of claim 2 wherein R.sup.2 is an optionally
substituted ring selected from phenyl, naphthyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl,
benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,
pyranyl, benzodioxolyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cyclobeptyl.
4. The compound of claim 3 wherein R.sup.2 is phenyl optionally
substituted with 1-5 substituents of halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, acetyl, C.sub.1-10-alkyl, C.sub.2-10-alkenyl,
C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl, C.sub.1-10-alkylamino-,
C.sub.1-10-dialkylamino-, C.sub.1-10-alkoxyl or a ring selected
from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl and
pyranyl, said ring optionally substituted with 1-5 substituents of
R.sup.7.
5. The compound of claim 1 wherein each of A.sup.1 and A.sup.2,
independently, is CH; one of A.sup.3 and A.sup.4 is N and the other
of A.sup.3 and A.sup.4 is CH or CR.sup.6; R.sup.1 is a ring
selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl,
pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,
isoquinazolinyl, phthalazinyl, thiophenyl, thienopyrimidinyl,
thienopyridinyl, furyl, pyrrolyl, pyrazolyl, pyrazolopyridinyl,
pyrazoliopyrimidinyl, imidazolyl, triazolyl, triazolopyrazinyl,
triazolopyridinyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl,
benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl and benzodioxolyl, said ring optionally
susbstituted with 1-5 substituents of R.sup.7; R.sup.2 is a ring
selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl,
isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,
piperazinyl and pyranyl, said ring optionally substituted with 1-5
substituents of R.sup.7; each R.sup.3, independently, is H; R.sup.4
is H or C.sub.1-4-alkyl; R.sup.5 is H, halo, haloalkyl,
C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl,
--NH--C.sub.1-6-alkyl, --N-di-C.sub.1-6-alkyl, CN, OH or NH.sub.2;
X is CHR.sup.6, C(.dbd.O) or O; Z is a cyclopropyl, cyclobutyl or
cyclopentyl ring wherein 0, 1 or 2 carbon atoms of the ring are,
independently, replaced with an oxygen atom and the ring optionally
substituted independently with 1-5 substituents of R.sup.7; and
each R.sup.6, independently, is halo, haloalkyl, C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH, NH.sub.2, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl or
R.sup.6 is a fully unsaturated or partially or fully unsaturated 5-
or 6-membered monocyclic or bicyclic ring formed of carbon atoms,
said ring optionally including 1-5 heteroatoms selected from O, N,
or S wherein said C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl,
the C.sub.1-6-alkyl portion of --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl and
--N-di-C.sub.1-6-alkyl and ring are optionally substituted with 1-5
substituents of R.sup.7.
6. The compound of claim 5 wherein ring Z is ##STR00051## wherein
R.sup.7 is as defined in claim 1; and p is 0, 1, 2, 3 or 4.
7. The compound of claim 1 having a general Formula II:
##STR00052## or a stereoisomer or pharmaceutically acceptable salt
thereof, wherein one of A.sup.2, A.sup.3 and A.sup.4 is N and the
other of A.sup.2, A.sup.3 and A.sup.4 is CH or CR.sup.6; A.sup.5 is
CH or N; R.sup.4 is H, halo or C.sub.1-6-alkyl; R.sup.5 is H, halo,
haloalkyl, C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH or N.sub.2, wherein the
C.sub.1-6alkyl and the C.sub.1-6-alkyl portion of
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl
and ---N-di-C.sub.1-6-alkyl are optionally substituted
independently with 1-5 substituents of R.sup.7; X is CHR.sup.6,
C(.dbd.O)or O; Y is CR.sup.7R.sup.7, NR.sup.7, S or O; Z is a
cyclopropyl, cyclobutyl or cyclopentyl ring wherein 0, 1 or 2
carbon atoms of the ring are, independently, replaced with an
oxygen atom and the ring optionally substituted independently with
1-5 substituents of R.sup.7; Z.sup.2 taken together with the carbon
atom to which A.sup.5 and Y are attached is a 4-, 5- or 6-membered
monocylic ring or a 8-, 9- or 10-membered bicyclic ring, said ring
formed of carbon atoms optionally including 1-3 heteroatoms if
monocylic or 1-5 heteroatoms if bicyclic, said heteroatoms selected
from N, O and S, and said ring optionally susbstituted with 1-5
substituents of R.sup.7; each R.sup.6, independently, is halo,
haloalkyl, C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH, NH.sub.2, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl or
R.sup.6 is a fully unsaturated or partially or fully unsaturated 5-
or 6-membered monocyclic or bicyclic ring formed of carbon atoms,
said ring optionally including 1-5 heteroatoms selected from O, N,
or S wherein said C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl,
the C.sub.1-6-alkyl portion of --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl and
--N-di-C.sub.1-6-alkyl and ring are optionally substituted with 1-5
substituents of R.sup.7; each R.sup.7, independently, is H, halo,
haloalkyl, CN, OH, NO.sub.2, NH.sub.2, acetyl, oxo,
C.sub.1-10-alkyl, C.sub.2-10-alkenyl, C.sub.2-10-alkynyl,
C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl or a fully saturated or
partially or fully unsaturated 3-8 membered monocyclic or a 6-12
membered bicyclic, said ring system formed of carbon atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,
wherein each of the C.sub.1-10-alkyl, C.sub.2-10-alkenyl,
C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl and ring of said ring
system is optionally substituted independently with 1-5
substituents of halo, haloalkyl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,
isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,
cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-thioalkoxyl, benzyl or phenyl; m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2, 3, 4 or 5.
8. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, selected from
(2R,3S)-3-((2-chloro-4-pyrimidinyl)amino)-4-(3,5-difluorophenyl)-1-(((4'S-
)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b-
]pyridin]-4'-yl)amino)-2-butanol;
(2R,3S)-4-(3,5-difluorophenyl)-1-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-di-
hydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-3-([1,2,4]t-
riazolo[4,3-a]pyrazin-8-ylamino)-2-butanol;
(2R,3S)-4-(3,5-difluorophenyl)-1-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-di-
hydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-3-(2-pyrimi-
dinylamino)-2-butanol;
3-((2S,3R)-4-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4--
yl) amino)-2-((2-fluorophenyl)amino)-3-hydroxybutyl)benzonitrile;
and
(2R,3S)-1-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane--
1,2-pyrano[2,3-b]pyridin]-4'-yl)amino)-4-(4-fluorophenyl)-3-(thieno[2,3-d]-
pyrimidin-4-ylamino)-2-butanol.
9. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound according to claim 1.
10. A method of treating Alzheimer's disease in a subject, the
method comprising administering to the subject an effective dosage
amount of a compound according to claim 1.
11. A method of treating Alzheimer's disease in a subject, the
method comprising administering to the subject an effective dosage
amount of the composition according to claim 1.
12. A method of reducing the formation of beta amyloid peptide in a
subject, the method comprising administering to the subject an
effective dosage amount of a compound according to claim 1.
13. A method of reducing the formation of beta amyloid peptide in a
subject, the method comprising administering to the subject an
effective dosage amount of the composition according to claim
9.
14. A method of reducing plaque on the brain of a subject, the
method comprising administering to the subject an effective dosage
amount of a compound according to claim 1.
15. A method of reducing plaque on the brain of a subject, the
method comprising administering to the subject an effective dosage
amount of the composition according to claim 9.
16. A method of treating mild cognitive impairment, Down's
syndrome, Hereditary cerebral hemorrhage with dutch-type
amyloidosis, cerebral amyloid angiopathy, degenerative dementia,
dementia associated with Parkinson's disease, dementia associated
with supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse lewy body type of Alzheimer's disease or a
combination thereof in a subject, the method comprising
administering to the subject an effective dosage amount of a
compound according to claim 1.
17. A method of treating mild cognitive impairment, Down's
syndrome, Hereditary cerebral hemorrhage with dutch-type
amyloidosis, cerebral amyloid angiopathy, degenerative dementia,
dementia associated with Parkinson's disease, dementia associated
with supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse lewy body type of Alzheimer's disease or a
combination thereof in a subject, the method comprising
administering to the subject an effective dosage amount of the
composition according to claim 9.
Description
RELATED APPICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/003,164, filed 14 Nov. 2007, which specification
is hereby incorporated here in by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates generally to pharmaceutically active
compounds, pharmaceutical compositions and methods of use thereof,
to treat Beta-Secretase mediated disorders, including Alzheimer's
disease, plaque formation and deposition on the brain and related
conditions.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) affects greater than 12 million
aging people worldwide. AD accounts for the majority of dementia
clinically diagnosed after the age of 60. AD is generally
characterized by the progressive decline of memory, reasoning,
judgement and orientation. As the disease progresses, motor,
sensory, and vocal abilities are affected until there is global
impairment of multiple cognitive functions. The loss of cognitive
function occurs gradually, typically leading to a diminished
cognition of one's self, family and friends. Patients with severe
cognitive impairment and/or diagnosed as end-stage AD are generally
bedridden, incontinent, and dependent on custodial care. After
initial diagnosis, the average survival period for the AD patient
is only about nine to ten years. Due to the incapacitating,
generally humiliating and ultimately fatal effects of AD, there is
a need to effectively treat AD upon diagnosis.
[0004] AD is characterized by two major physiological changes in
the brain. The first change, beta amyloid plaque formation,
supports the "amyloid cascade hyposthesis" which alleges that AD is
caused by the formation of characteristic beta amyloid deposits
(commonly referred to as beta amyloid "plaques" or "plaque
deposits") in the brain and in cerebral blood vessels (beta amyloid
angiopathy). The second change in AD is the formation of
intraneuronal tangles, consisting of an aggregate form of the
protein tau. Amyloid plaques are thought to be specific for AD,
while intraneuronal tangles are also found in other
dementia-inducing disorders. Joachim et al., Alz. Dis. Assoc. Dis.,
6:7-34 (1992).
[0005] It's been hypothesized that beta amyloid protein (also
commonly referred to and referred to herein as amyloid-beta peptide
or A-beta peptide) formation is a causative precursor or factor in
plaque formation and consequently, the development and/or
progression of AD. Deposition of A-beta peptide in areas of the
brain responsible for areas of cognition, is believed to be a major
factor in the development and/or progression of AD. Several lines
of evidence indicate that progressive cerebral deposition of
beta-amyloid peptide (A-beta) plays a seminal role in the
pathogenisis of AD and can precede cognitive symptoms by years or
even decades. Selkoe, Neuron, 6:487 (1991). Release of A-beta from
neuronal cells grown in culture and the presence of A-beta in
cerebrospinal fluid (CSF) of both normal individuals and AD
patients has been demonstrated. Seubert et al., Nature, 359:325-327
(1992). In addition, autopsies of AD patients have revealed large
numbers of lesions comprising these 2 factors in areas of the human
brain believed to be important for memory and cognition. Smaller
numbers of these lesions in a more restricted anatomical
distribution are found in the brains of most aged humans who do not
have clinical symptoms of AD. Amyloid containing plaques and
vascular amyloid angiopathy were also found in the brains of
individuals with Down's Syndrome, Herditary Cerebral Hemorrhage
with Amyloidosis of the Dutch-type (HCHWA-D), and other
neurodegenerative disorders.
[0006] Beta amyloid plaques are primarily composed of amyloid beta
peptide (A-beta peptide). A-beta peptide is derived from the
proteolytic cleavage of a large transmembrane amyloid precursor
protein (APP), and is a peptide ranging in about 39-42 amino acids.
A-beta 42 (42 amino acids long) is thought to be the major
component of these plaque deposits. Citron, Trends in
Pharmacological Sciences, 25(2):92-97 (2004). Several aspartyl
proteases are thought to be involved in the processing or cleavage
of APP, resulting in the formation of A-beta peptide. Beta
secretase (BACE, also commonly referred to as memapsin) is thought
to first cleave APP to generate two fragments of the A-beta
peptide: (1) a first N-terminus fragment and (2) a second C-99
fragment, which is subsequently cleaved by gamma secretase to
generate the C-terminus fragment of the A-beta peptide. APP has
also found to be cleaved by alpha-secretase to produce alpha-sAPP,
a secreted form of APP that does not result in beta-amyloid plaque
formation. This alternate pathway precludes the formation of A-beta
peptide. A decription of the proteolytic processing fragments of
APP is found, for example, in U.S. Pat. Nos. 5,441,870, 5,712,130
and 5,942,400.
[0007] BACE is an aspartyl protease enzyme comprising 501 amino
acids and responsible for processing APP at the beta-secretase
specific cleavage site. BACE is present in two forms, BACE 1 and
BACE 2, designated as such depending upon the specific cleavage
site of APP. Beta secretase is described in Sinha et al., Nature,
402:537-554 (1999) (p 510) and PCT application WO 2000/17369. It
has been proposed that A-beta peptide accumulates as a result of
APP processing by BACE. Moreover, in vivo processing of APP at the
beta secretase cleavage site is thought to be a rate-limiting step
in A-beta production. Sabbagh, M. et al., Alz. Dis. Rev. 3:1-19
(1997). Thus, inhibition of the BACE enzyme activity is thought to
be desirable for the treatment of AD.
[0008] Studies have shown that the inhibition of BACE may be linked
to the treatment of AD. BACE1 knockout mice have failed to produce
A-beta, and present a normal phenotype. When crossed with
transgenic mice that over express APP, the progeny show reduced
amounts of A-beta in brain extracts as compares with control
animals (Luo et al., Nature Neuroscience, 4:231-232 (2001)). This
evidence further supports the concept that inhibition of beta
secretase activity and a corresponding reduction of A-beta in the
brain should provide a therapeutic method for treating AD and other
beta amyloid or plaque related disorders.
[0009] Researchers have taken several approaches to treat AD and
plaque-related disorders. One approach has been to reduce the
formation of plaque on the brain. Particularly, a common approach
has been to inhibit the activity of beta secretase. For example,
each of the following PCT publications: WO 03/045913, WO 04/043916,
WO 03/002122, WO 03/006021, WO 03/002518, WO 04/024081, WO
03/040096, WO 04/050619, WO 04/080376, WO 04/099376, WO 05/004802,
WO 04/080459, WO 04/062625, WO 04/042910, WO 05/004803, WO
05/005374, WO 03/106405, WO 03/062209, WO 03/030886, WO 02/002505,
WO 01/070671, WO 03/057721, WO 03/006013, WO 03/037325, WO
04/094384, WO 04/094413, WO 03/006423, WO 03/050073, WO 03/029169
and WO 04/000821, describe inhibitors of beta secretase, useful for
treating AD and other beta-secretase mediated disorders.
BRIEF DESCRIPTION OF THE INVENTION
[0010] The present invention provides a new class of compounds
useful for the modulation of beta secretase activity. To that end,
the compounds of the invention are useful for the regulation or
reduction of the formation of A-beta peptide and consequently, the
reduction of beta amyloid plaque formation on the brain.
Accordingly, the compounds are useful for the treatment of
Alzheimer's disease and other beta secretase mediated
disorders.
[0011] The compounds provided by the invention, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable
salts, derivatives or prodrugs thereof, are generally defined by
Formula I
##STR00002##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, A.sup.1,
A.sup.2, A.sup.3, A.sup.4, X and Z are as described below. The
invention also provides procedures for making compounds of Formula
I, as well as intermediates useful in such procedures.
[0012] The invention further provides for the use of these
compounds for therapeutic, prophylactic, acute and/or chronic
treatment of beta secretase mediated diseases, such as those
described herein. For example, the compounds are useful for the
prophylaxis and treatment of AD and other diseases or conditions
involving amyloid plaque formation on the brain.
[0013] The invention also provides pharmaceutical compositions,
which comprise one or more compounds of the invention, methods for
the treatment of beta secretase mediated diseases, such as AD,
using the compounds and compositions of the invention, and
intermediates and processes useful for the preparation of the
compounds of the invention. The invention also provides use of the
pharmaceutical composition or medicament, containing one or more of
the compounds of the invention, to attenuate, alleviate, or treat
disorders through inhibition of beta secretase. For example, and in
one embodiment, the invention provides a pharmaceutical composition
comprising an effective dosage amount of a compound of Formula I in
association with at least one pharmaceutically acceptable
excipient.
[0014] The foregoing merely summarizes certain aspects of the
invention and is not intended, nor should it be construed, as
limiting the invention in any way. All patents and other
publications recited herein are hereby incorporated by reference in
their entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0015] In one embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable
salts, derivatives or prodrugs thereof, are generally defined
by
##STR00003##
R.sup.1 is a partially or fully unsaturated 4-8 membered monocyclic
or 6-12 membered bicyclic ring, said ring formed of carbon atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,
and wherein said ring is optionally substituted independently with
one or more substituents of oxo, R.sup.7, NR.sup.7R.sup.7,
OR.sup.7, SR.sup.7, C(O)R.sup.7, OC(O)R.sup.7, COOR.sup.7,
C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7;
[0016] R.sup.2 is a partially or fully saturated or fully
unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring,
said ring formed of carbon atoms optionally including 1-3
heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said
heteroatoms selected from O, N, or S, and wherein said ring is
optionally substituted independently with one or more substituents
of oxo, R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7, C(O)R.sup.7,
OC(O)R.sup.7, COOR.sup.7, C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7;
[0017] each R.sup.3, independently, is H, haloalkyl, CN,
C.sub.1-6-alkyl, C.sub.2-8-alkenyl, C.sub.2-8-alkynyl,
C.sub.3-8-cycloalkyl or C.sub.4-8-cycloalkenyl, each of the
C.sub.1-6-alkyl, C.sub.2-8-alkenyl, C.sub.2-8C.sub.3-8-cycloalkyl
and C.sub.4-8-cycloalkenyl optionally comprising 1-2 heteroatoms
selected from N, O and S and optionally substituted with 1-5
substituents of R.sup.7;
[0018] R.sup.4 is H, halo or C.sub.1-6-alkyl;
[0019] R.sup.5 is H, halo, haloalkyl, oxo, C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH or NH.sub.2, wherein the
C.sub.1-6-alkyl and the C.sub.1-6-alkyl portion of
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl
and --N-di-C.sub.1-6-alkyl are optionally substituted independently
with 1-5 substituents of R.sup.7;
[0020] each of A.sup.1, A.sup.2, A.sup.3 and A.sup.4,
independently, is N, CH or CR.sup.6, provided that no more than two
of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 is N;
[0021] X is CHR.sup.6, CR.sup.6R.sup.6, C(.dbd.O), O, NR.sup.6, or
S(O).sub.o wherein o is 0, 1 or 2;
[0022] Z is a 3-6 membered spirocyclic ring formed of carbon atoms
optionally including 1-3 heteroatoms selected from O, N and S and
optionally substituted independently with 1-3 substituents of
R.sup.7;
[0023] each R.sup.6, independently, is halo, haloalkyl,
C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl,
--NH--C.sub.1-6-alkyl, --N-di-C.sub.1-6-alkyl, CN, OH, NH.sub.2,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl or
C.sub.4-8-cycloalkenyl, wherein the C.sub.1-6-alkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.4-8-cycloalkenyl and the C.sub.1-6-alkyl portion of
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl
and --N-di-C.sub.1-6-alkyl are optionally substituted with 1-5
substituents of R.sup.7;
[0024] or R.sup.6 is a fully unsaturated or partially or fully
unsaturated 5- or 6-membered monocyclic or bicyclic ring formed of
carbon atoms, said ring optionally including 1-5 heteroatoms
selected from O, N, or S and optionally substituted with one or
more substituents of R.sup.7; and
[0025] each R.sup.7, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, acetyl, oxo, C.sub.1-10-alkyl,
C.sub.2-10-alkenyl, C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl,
C.sub.4-10-cycloalkyl, C.sub.1-10-alkylamino-,
C.sub.1-10-dialkylamino-, C.sub.1-10-alkoxyl,
C.sub.1-10-thioalkoxyl or a fully saturated or partially or fully
unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic
ring, said ring formed of carbon atoms optionally including 1-3
heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said
heteroatoms selected from O, N, or S, wherein each of the
C.sub.1-10-alkyl, C.sub.2-10-alkenyl, C.sub.2-10-alkynyl,
C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl and ring is optionally
substituted independently with 1-5 substituents of halo, haloalkyl,
CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,
propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl,
hexyl, cyclohexyl, C.sub.1-10-alkylamino-,
C.sub.1-10-dialkylamino-, C.sub.1-10-thioalkoxyl, benzyl or phenyl.
The compound of claim 1 wherein R.sup.1 is an optionally
substituted ring selected from phenyl, naphthyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, thienopyrimidinyl, thienopyridinyl, furyl, pyrrolyl,
pyrazolyl, pyrazolopyridinyl, pyrazoliopyrimidinyl, imidazolyl,
triazolyl, triazolopyrazinyl, triazolopyridinyl, tetrazolyl,
thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl,
oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl and
benzodioxolyl.
[0026] In another embodiment of the invention, the compounds of
Formula I include compounds wherein A.sup.1 is N, in conjunction
with any of the above or below embodiments.
[0027] In another embodiment of the invention, the compounds of
Formula I include compounds wherein A.sup.1 is CH, in conjunction
with any of the above or below embodiments.
[0028] In another embodiment of the invention, the compounds of
Formula I include compounds wherein A.sup.1 is CR.sup.6 in
conjunction with any of the above or below embodiments.
[0029] In another embodiment of the invention, the compounds of
Formula I include compounds wherein A.sup.2 is N, in conjunction
with any of the above or below embodiments.
[0030] In another embodiment of the invention, the compounds of
Formula I include compounds wherein A.sup.2 is CH, in conjunction
with any of the above or below embodiments.
[0031] In another embodiment of the invention, the compounds of
Formula I include compounds wherein A.sup.2 is CR.sup.6, in
conjunction with any of the above or below embodiments.
[0032] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each of A.sup.1 and A.sup.2,
independently, is CH in conjunction with any of the above or below
embodiments.
[0033] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each of A.sup.1, A.sup.2,
A.sup.3 and A.sup.4, independently, is CH in conjunction with any
of the above or below embodiments.
[0034] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each of A.sup.1 and A.sup.2,
independently, is CR.sup.6 in conjunction with any of the above or
below embodiments.
[0035] In another embodiment of the invention, the compounds of
Formula I include compounds wherein one of A.sup.1 and A.sup.2,
independently, is N and the other of one of A.sup.1 and A.sup.2,
independently, is CR.sup.6 in conjunction with any of the above or
below embodiments.
[0036] In another embodiment of the invention, the compounds of
Formula I include compounds wherein one of A.sup.1 is CH and one of
A.sup.2, A.sup.3 and A.sup.4, independently, is N and the other
three of A.sup.2, A.sup.3 and A.sup.4, independently, is CH or
CR.sup.6 in conjunction with any of the above or below
embodiments.
[0037] In another embodiment of the invention, the compounds of
Formula I include compounds wherein one of A.sup.1, A.sup.2,
A.sup.3 and A.sup.4, independently, is N and the other three of
A.sup.1, A.sup.2, A.sup.3 and A.sup.4, independently, is CH or
CR.sup.6 in conjunction with any of the above or below
embodiments.
[0038] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.1 is a partially or fully
unsaturated 4-8 membered monocyclic or 6-12 membered bicyclic ring,
said ring formed of carbon atoms optionally including 1-3
heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said
heteroatoms selected from O, N, or S, and wherein said ring is
optionally substituted independently with one or more substituents
of oxo, R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7, C(O)R.sup.7,
OC(O)R.sup.7, COOR.sup.7, C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7, in
conjunction with any of the above or below embodiments.
[0039] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.1 is a ring selected from
phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,
isoquinazolinyl, phthalazinyl, thiophenyl, thienopyrimidinyl,
thienopyridinyl, furyl, pyrrolyl, pyrazolyl, pyrazolopyridinyl,
pyrazolopyrimidinyl, imidazolyl, triazolyl, triazolopyrazinyl,
triazolopyridinyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl,
benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl and benzodioxolyl, said ring optionally
susbstituted with 1-5 substituents of R.sup.7, in conjunction with
any of the above or below embodiments.
[0040] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.1 is a ring selected from
phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl,
thienopyrimidinyl, thienopyridinyl, furyl, pyrazolyl,
pyrazolopyridinyl, pyrazolopyrimidinyl, imidazolyl,
triazolopyrazinyl, triazolopyridinyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl,
isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl and benzodioxolyl, said ring
optionally susbstituted with 1-5 substituents of R.sup.7, in
conjunction with any of the above or below embodiments.
[0041] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.2 is a partially or fully
saturated or fully unsaturated 3-8 membered monocyclic or 6-12
membered bicyclic ring, said ring formed of carbon atoms optionally
including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said heteroatoms selected from O, N, or S, and wherein
said ring is optionally substituted independently with one or more
substituents of oxo, R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7,
C(O)R.sup.7, OC(O)R.sup.7, COOR.sup.7,
C(O)NR.sup.7R.sup.6NR.sup.7C(O)R.sup.7, NR.sup.7C(O)NR.sup.7R,
NR.sup.7(COOR.sup.7), OC(O)NR.sup.7R.sup.7,
S(O).sub.2NR.sup.7R.sup.7, NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or
NR.sup.7S(O).sub.2R.sup.7, in conjunction with any of the above or
below embodiments.
[0042] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.2 is phenyl, naphthyl,
pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl,
benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,
pyranyl, dioxozinyl, benzodioxolyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl, each of is optionally
substituted independently with one or more substituents of oxo,
R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7, C(O)R.sup.7,
OC(O)R.sup.7, COOR.sup.7, C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7, in
conjunction with any of the above or below embodiments.
[0043] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.2 is an optionally
substituted ring selected from phenyl, naphthyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl,
benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,
pyranyl, benzodioxolyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, in conjunction with any of the above or
below embodiments.
[0044] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.2 is phenyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl,
pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,
oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,
indolyl, isoindolyl, benzofuranyl, benzimidazolyl, pyrrolidinyl or
benzodioxolyl, each of is optionally substituted independently with
one or more substituents of oxo, R.sup.7, NR.sup.7R.sup.7,
OR.sup.7, SR.sup.7, C(O)R.sup.7, OC(O)R.sup.7, COOR.sup.7,
C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7, in
conjunction with any of the above or below embodiments.
[0045] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.2 is phenyl or
benzodioxolyl, each of is optionally substituted independently with
one or more substituents of oxo, R.sup.7, NR.sup.7R.sup.7,
OR.sup.7, SR.sup.7, C(O)R.sup.7, OC(O)R.sup.7, COOR.sup.7,
C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7, S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7, the
above or below embodiments.
[0046] In another embodiment of the invention, the compounds of
Formula I include compounds wherein R.sup.2 is phenyl optionally
substituted with 1-5 substituents of halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, acetyl, C.sub.1-10-alkyl, C.sub.2-10-alkenyl,
C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl, C.sub.1-10-alkylamino-,
C.sub.1-10-dialkylamino-, C.sub.1-10-alkoxyl or a ring selected
from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl and
pyranyl, said ring optionally substituted with 1-5 substituents of
R.sup.7, in conjunction with any of the above or below
embodiments.
[0047] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each R.sup.3, independently, is
H, haloalkyl, CN, C.sub.1-6-alkyl, C.sub.2-8-alkenyl,
C.sub.2-8-alkynyl, C.sub.3-8-cycloalkyl or C.sub.4-8-cycloalkenyl,
each of the C.sub.1-6-alkyl, C.sub.2-8-alkenyl, C.sub.2-8-alkynyl,
C.sub.3-8-cycloalkyl and C.sub.4-8-cycloalkenyl optionally
comprising 1-2 heteroatoms selected from N, O and S and optionally
substituted with 1-5 substituents of R.sup.7, in conjunction with
any of the above or below embodiments.
[0048] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each R.sup.3, independently, is
H, haloalkyl, CN, C.sub.1-10-alkyl, C.sub.2-10-alkenyl or
C.sub.2-10-alkynyl, in conjunction with any of the above or below
embodiments.
[0049] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each R.sup.3, independently, is
H, haloalkyl or C.sub.1-10-alkyl, in conjunction with any of the
above or below embodiments.
[0050] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each R.sup.3, independently, is
H, in conjunction with any of the above or below embodiments.
[0051] In another embodiment of the invention, the compounds of
Formula I include compounds wherein each of A.sup.1 and A.sup.2,
independently, is CH;
[0052] one of A.sup.3 and A.sup.4 is N and the other of A.sup.3 and
A.sup.4 is CH or CR.sup.6;
[0053] R.sup.1 is a ring selected from phenyl, naphthyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, thienopyrimidinyl, thienopyridinyl, furyl, pyrrolyl,
pyrazolyl, pyrazolopyridinyl, pyrazoliopyrimidinyl, imidazolyl,
triazolyl, triazolopyrazinyl, triazolopyridinyl, tetrazolyl,
thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,
oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl,
oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl and
benzodioxolyl, said ring optionally susbstituted with 1-5
substituents of R.sup.7;
[0054] R.sup.2 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl,
oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,
piperidinyl, piperazinyl and pyranyl, said ring optionally
substituted with 1-5 substituents of R.sup.7;
[0055] each R.sup.3, independently, is H;
[0056] R.sup.4 is H or C.sub.1-4-alkyl;
[0057] R.sup.5 is H, halo, haloalkyl, C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH or NH.sub.2;
[0058] X is CHR.sup.6, C(.dbd.O) or O;
[0059] Z is a cyclopropyl, cyclobutyl or cyclopentyl ring wherein
0, 1 or 2 carbon atoms of the ring are, independently, replaced
with an oxygen atom and the ring optionally substituted
independently with 1-5 substituents of R.sup.7; and
[0060] each R.sup.6, independently, is halo, haloalkyl,
C.sub.16-alkyl, --O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl,
--NH--C.sub.1-6-alkyl, --N-di-C.sub.1-6-alkyl, CN, OH, NH.sub.2,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.4-8-cycloalkenyl or R.sup.6 is a fully unsaturated or
partially or fully unsaturated 5- or 6-membered monocyclic or
bicyclic ring formed of carbon atoms, said ring optionally
including 1-5 heteroatoms selected from O, N, or S wherein said
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl, the C.sub.1-6-alkyl
portion of --O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl,
--NH--C.sub.1-6-alkyl and --N-di-C.sub.1-6-alkyl and ring are
optionally substituted with 1-5 substituents of R.sup.7, in
conjunction with any of the above or below embodiments.
[0061] In another embodiment of the invention, there are provided
compounds, including stereoisomers, tautomers, solvates,
pharmaceutically acceptable salts, derivatives or prodrugs thereof,
generally defined by Formula II
##STR00004##
wherein [0062] one of A.sup.2, A.sup.3 and A.sup.4 is N and the
other of A.sup.2, A.sup.3 and A.sup.4 is CH or CR.sup.6;
[0063] A.sup.5 is CH or N;
[0064] R.sup.4 is H, halo or C.sub.1-6-alkyl;
[0065] R.sup.5 is H, halo, haloalkyl, C.sub.1-6-alkyl,
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, CN, OH or NH.sub.2, wherein the
C.sub.1-6-alkyl and the C.sub.1-6-alkyl portion of
--O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl
and --N-di-C.sub.1-6-alkyl are optionally substituted independently
with 1-5 substituents of R.sup.7;
[0066] X is CHR.sup.6, C(.dbd.O) or O;
[0067] Y is CR.sup.7R.sup.7, N, NR.sup.7, S or O;
[0068] Z is a cyclopropyl, cyclobutyl or cyclopentyl ring wherein
0, 1 or 2 carbon atoms of the ring are, independently, replaced
with an oxygen atom and the ring optionally substituted
independently with 1-5 substituents of R.sup.7;
[0069] Z.sup.2 taken together with the carbon atom to which A.sup.5
and Y are attached is a 4-, 5- or 6-membered monocylic ring or a
8-, 9- or 10-membered bicyclic ring, said ring formed of carbon
atoms optionally including 1-3 heteroatoms if monocylic or 1-5
heteroatoms if bicyclic, said heteroatoms selected from N, O and S,
and said ring optionally susbstituted with 1-5 substituents of
R.sup.7;
[0070] each R.sup.6, independently, is halo, haloalkyl,
C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl, --S--C.sub.1-6alkyl,
--NH--C.sub.1-6-alkyl, --N-di-C.sub.1-6-alkyl, CN, OH, NH.sub.2,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.4-8-cycloalkenyl or R.sup.6 is a fully unsaturated or
partially or fully unsaturated 5- or 6-membered monocyclic or
bicyclic ring formed of carbon atoms, said ring optionally
including 1-5 heteroatoms selected from O, N, or S wherein said
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl, the C.sub.1-6-alkyl
portion of --O--C.sub.1-6-alkyl, --S--C.sub.1-6-alkyl,
--NH--C.sub.1-6-alkyl and --N-di-C.sub.1-6-alkyl and ring are
optionally substituted with 1-5 substituents of R.sup.7;
[0071] each R.sup.7, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, acetyl, oxo, C.sub.1-10-alkyl,
C.sub.2-10-alkenyl, C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl,
C.sub.4-10-cycloalkenyl, C.sub.1-10-alkylamino-,
C.sub.1-10-dialkylamino-, C.sub.1-10-alkoxyl,
C.sub.1-10-thioalkoxyl or a fully saturated or partially or fully
unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic,
said ring system formed of carbon atoms optionally including 1-3
heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said
heteroatoms selected from O, N, or S, wherein each of the
C.sub.1-10-alkyl, C.sub.2-10-alkenyl, C.sub.2-10-alkynyl,
C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl and ring of said ring
system is optionally substituted independently with 1-5
substituents of halo, haloalkyl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,
isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,
cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-thioalkoxyl, benzyl or phenyl;
[0072] m is 0, 1, 2, 3 or 4; and
[0073] n is 0, 1, 2, 3, 4 or 5.
[0074] In another embodiment of the invention, the compounds of
Formula II include compounds wherein ring Z.sup.2 is a partially or
fully unsaturated 4-8 membered monocyclic or 6-12 membered bicyclic
ring, said ring formed of carbon atoms optionally including 1-3
heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said
heteroatoms selected from O, N, or S, and wherein said ring is
optionally substituted independently with one or more substituents
of oxo, R.sup.7, NR.sup.7R.sup.7, OR.sup.7, SR.sup.7, C(O)R.sup.7,
OC(O)R.sup.7, COOR.sup.7, C(O)NR.sup.7R.sup.7, NR.sup.7C(O)R.sup.7,
NR.sup.7C(O)NR.sup.7R.sup.7, NR.sup.7(COOR.sup.7),
OC(O)NR.sup.7R.sup.7S(O).sub.2NR.sup.7R.sup.7,
NR.sup.7S(O).sub.2NR.sup.7R.sup.7 or NR.sup.7S(O).sub.2R.sup.7, in
conjunction with any of the above or below embodiments.
[0075] In another embodiment of the invention, the compounds of
Formula II include compounds wherein Z.sup.2 is a ring selected
from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,
isoquinazolinyl, phthalazinyl, thiophenyl, thienopyrimidinyl,
thienopyridinyl, furyl, pyrrolyl, pyrazolyl, pyrazolopyridinyl,
pyrazolopyrimidinyl, imidazolyl, triazolyl, triazolopyrazinyl,
triazolopyridinyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl,
benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl, pyrazolinyl, cyclobutene and benzodioxolyl, said ring
optionally susbstituted with 1-5 substituents of R.sup.7, in
conjunction with any of the above or below embodiments.
[0076] In another embodiment of the invention, the compounds of
Formula II include compounds wherein ring Z.sup.2 is a ring
selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
thiophenyl, thienopyrimidinyl, thienopyridinyl, furyl, pyrazolyl,
pyrazolopyridinyl, pyrazolopyrimidinyl, imidazolyl,
triazolopyrazinyl, triazolopyridinyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl,
isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl and benzodioxolyl, said ring
optionally susbstituted with 1-5 substituents of R.sup.7, in
conjunction with any of the above or below embodiments.
[0077] In another embodiment of the invention, the compounds of
Formula II include compounds wherein A.sup.5 is CH or N, in
conjunction with any of the above or below embodiments.
[0078] In another embodiment of the invention, the compounds of
Formula II include compounds wherein A.sup.5 is N, in conjunction
with any of the above or below embodiments.
[0079] In another embodiment of the invention, the compounds of
Formula II include compounds wherein A.sup.5 is CH, in conjunction
with any of the above or below embodiments.
[0080] In another embodiment of the invention, the compounds of
Formula II include compounds wherein Y is CR.sup.7R.sup.7,
NR.sup.7, S or O, in conjunction with any of the above or below
embodiments.
[0081] In another embodiment of the invention, the compounds of
Formula II include compounds wherein Y is CR.sup.7R.sup.7, in
conjunction with any of the above or below embodiments.
[0082] In another embodiment of the invention, the compounds of
Formula II include compounds wherein Y is CHR.sup.7 NH, S or O, in
conjunction with any of the above or below embodiments.
[0083] In another embodiment of the invention, the compounds of
Formula II include compounds wherein Y is NR.sup.7, in conjunction
with any of the above or below embodiments.
[0084] In another embodiment of the invention, the compounds of
Formula II include compounds wherein Y is S or O, in conjunction
with any of the above or below embodiments.
[0085] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein ring Z is
##STR00005##
and wherein R.sup.7 is H, halo, haloalkyl, CN, OH, NO.sub.2,
NH.sub.2, acetyl, oxo, C.sub.1-10-alkyl, C.sub.2-10-alkenyl,
C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl or a fully saturated or
partially or fully unsaturated 3-8 membered monocyclic or a 6-12
membered bicyclic, said ring system formed of carbon atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,
wherein each of the C.sub.1-10-alkyl, C.sub.2-10-alkenyl,
C.sub.2-10-alkynyl, C.sub.3-10-cycloalkyl, C.sub.4-10-cycloalkenyl,
C.sub.1-10-alkylamino, C.sub.1-10-dialkylamino-,
C.sub.1-10-alkoxyl, C.sub.1-10-thioalkoxyl and ring of said ring
system is optionally substituted independently with 1-5
substituents of halo, haloalkyl, CN, NO.sub.2, NH.sub.2, OH, oxo,
methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,
isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,
cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl,
C.sub.1-10-alkylamino-, C.sub.1-10-dialkylamino-,
C.sub.1-10-thioalkoxyl, benzyl or phenyl, and p is 0, 1, 2, 3 or 4,
in conjunction with any of the above or below embodiments.
[0086] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.4 is H, halo or
C.sub.1-6-alkyl, in conjunction with any of the above or below
embodiments.
[0087] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.4 is H or
C.sub.1-6-alkyl, in conjunction with any of the above or below
embodiments.
[0088] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.4 is H, in
conjunction with any of the above or below embodiments.
[0089] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.5 is H, halo,
haloalkyl, oxo, C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6alkyl, --N-di-C.sub.1-6-alkyl,
acetyl, CN, OH or NH.sub.2, wherein the C.sub.1-6-alkyl and the
C.sub.1-6-alkyl portion of --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl and
--N-di-C.sub.1-6-alkyl alkyl are optionally substituted
independently with 1-5 substituents of R.sup.7, in conjunction with
any of the above or below embodiments.
[0090] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.5 is H, halo,
haloalkyl, C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--S--C.sub.1-6-alkyl, --NH--C.sub.1-6-alkyl,
--N-di-C.sub.1-6-alkyl, acetyl, CN, OH or NH.sub.2, in conjunction
with any of the above or below embodiments.
[0091] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.5 is H, halo,
haloalkyl, C.sub.1-6-alkyl, --O--C.sub.1-6-alkyl,
--NH--C.sub.1-6-alkyl, CN or OH, in conjunction with any of the
above or below embodiments.
[0092] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein R.sup.5 is H, in
conjunction with any of the above or below embodiments.
[0093] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein A.sup.3 is N, in
conjunction with any of the above or below embodiments.
[0094] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein A.sup.3 is CH, in
conjunction with any of the above or below embodiments.
[0095] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein A.sup.3 is CR.sup.6 in
conjunction with any of the above or below embodiments.
[0096] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein A.sup.4 is N, in
conjunction with any of the above or below embodiments.
[0097] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein A.sup.4 is CH, in
conjunction with any of the above or below embodiments.
[0098] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein A.sup.4 is CR.sup.6, in
conjunction with any of the above or below embodiments.
[0099] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein each of A.sup.3 and
A.sup.4, independently, is CH in conjunction with any of the above
or below embodiments.
[0100] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein each of A.sup.3 and
A.sup.4, independently, is CR.sup.6 in conjunction with any of the
above or below embodiments.
[0101] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein one of A.sup.3 and
A.sup.4, independently, is N and the other one of A.sup.3 and
A.sup.4, independently, is CR.sup.6 in conjunction with any of the
above or below embodiments.
[0102] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein one of A.sup.3 and
A.sup.4, independently, is N and the other one of A.sup.3 and
A.sup.4, independently, is CH in conjunction with any of the above
or below embodiments.
[0103] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is CHR.sup.6,
CR.sup.6R.sup.6, C(.dbd.O), O, NR.sup.6, or S(O).sub.o wherein o is
0, 1 or 2, in conjunction with any of the above or below
embodiments.
[0104] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is CHR.sup.6, in
conjunction with any of the above or below embodiments.
[0105] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is CR.sup.6R.sup.6, in
conjunction with any of the above or below embodiments.
[0106] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is C(.dbd.O), in
conjunction with any of the above or below embodiments.
[0107] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is O, in conjunction
with any of the above or below embodiments.
[0108] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is NR.sup.6, in
conjunction with any of the above or below embodiments.
[0109] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is S(O).sub.o wherein
o is 0, 1 or 2, in conjunction with any of the above or below
embodiments.
[0110] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is CHR.sup.6, O or
NR.sup.6, in conjunction with any of the above or below
embodiments.
[0111] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein X is CHR.sup.6,
C(.dbd.O) or O, in conjunction with any of the above or below
embodiments.
[0112] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein ring Z is a 3-6 membered
spirocyclic ring formed of carbon atoms optionally including 1-3
heteroatoms selected from O, N and S and optionally substituted
independently with 1-3 substituents of R.sup.7, in conjunction with
any of the above or below embodiments.
[0113] In another embodiment of the invention, the compounds of
Formulas I or II include compounds wherein ring Z is a cyclopropyl,
cyclobutyl or cyclopentyl ring wherein 0, 1 or 2 carbon atoms of
the ring are, independently, replaced with an oxygen atom and the
ring optionally substituted independently with 1-5 substituents of
R.sup.7, in conjunction with any of the above or below
embodiments.
[0114] In another embodiment, the invention provides each of the
Exemplary compounds, and stereoisomers, tautomers, solvates,
pharmaceutically acceptable salts, derivatives or prodrugs thereof,
and synthetic intermediates at each step of the process of making
compounds of Formulas I or II, which are generally described
herein.
Definitions
[0115] The following definitions should assist in understanding the
invention described herein.
[0116] The term "comprising" is meant to be open ended, i.e., all
encompassing and non-limiting. Comprising is intended to include
each and every indicated component while not excluding any other
components or elements.
[0117] The term "C.sub..alpha.-.beta.alkyl", when used either alone
or within other terms such as "haloalkyl" and "alkylamino",
embraces linear or branched radicals having .alpha. to .beta.
number of carbon atoms (such as C.sub.1-C.sub.10). One or more
carbon atoms of the "alkyl" radical may be substituted, such as
with a cycloalkyl moeity. Examples of "alkyl" radicals include
methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
ethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,
n-propyl, isopropyl, n-butyl, cyclopropylbutyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The
term "alkylenyl" embraces bridging divalent alkyl radicals such as
methylenyl and ethylenyl.
[0118] The term "alkenyl", when used alone or in combination,
embraces linear or branched radicals having at least one
carbon-carbon double bond in a moiety having between two and ten
carbon atoms. Included within alkenyl radicals are "lower alkenyl"
radicals having two to about six carbon atoms and, for example,
those radicals, having two to about four carbon atoms. Examples of
alkenyl radicals include, without limitation, ethenyl, propenyl,
allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl"
and "lower alkenyl", embrace radicals having "cis" and "trans"
orientations, or alternatively, "E" and "Z" orientations, as
appreciated by those of ordinary skill in the art.
[0119] The term "alkynyl", when used alone or in combination,
denotes linear or branched radicals having at least one
carbon-carbon triple bond and having two to ten carbon atoms.
Examples of alkynyl radicals include "lower alkynyl" radicals
having two to about six carbon atoms and, for example, lower
alkynyl radicals having two to about four carbon atoms. Examples of
such radicals include, without limitation, ethynyl, propynyl
(propargyl), butynyl, and the like.
[0120] The term "C.sub..alpha.-.beta.-alkyl",
"C.sub..alpha.-.beta.-alkenyl" and "C.sub..alpha.-.beta.-alkynyl" ,
when used with other terms such as "wherein 1, 2 or 3 carbon atoms
of said C.sub..alpha.-.beta.-alkyl, C.sub..alpha.-.beta.-alkenyl or
C.sub.2.alpha.-.beta.-alkynyl is optionally replaced with a
heteroatom selected from O, S, S(O), S(O).sub.2 and N" embraces
linear or branched radicals wherein one or more of the carbon atoms
may be replaced with a heteroatom. Examples of such "alkyl"
radicals include --O-methyl, --O-ethyl, --CH.sub.2--O--CH.sub.3,
--CH.sub.2CH.sub.2--O--CH.sub.3, --NH--CH.sub.2,
--CH.sub.2CH.sub.2--N(CH.sub.3)--CH.sub.3,
--S--(CH.sub.2).sub.3CH.sub.2, --CH.sub.2CH.sub.2--S--CH.sub.3 and
the like. Accordingly, such radicals also include radicals
encompassed by --OR.sup.7 where R.sup.7 may be defined as a
C.sub..alpha.-.beta.-alkyl. Examples of such "alkenyl" radicals
include --CH.dbd.CH--O--CH.sub.3, --NH--CH.sub.2CH.dbd.CH.sub.2,
--S--CH.sub.2CH.sub.2CH.dbd.CHCH.sub.3 and the like. Simlar
examples exist for such "alkynyl" radicals, as appreciated by those
skilled in the art.
[0121] The term "C.sub..alpha.-.beta.-alkoxyl" when used alone or
in combination, embraces linear or branched oxygen-containing alkyl
radicals each having .alpha. to .beta. number of carbon atoms (such
as C.sub.1-C.sub.10). The terms "alkoxy" and "alkoxyl", when used
alone or in combination, embraces linear or branched
oxygen-containing radicals each having alkyl and substituted alkyl
portions of one or more carbon atoms. Examples of such radicals
include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy
radicals may be further substituted with one or more halo atoms,
such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals
or with other substitution. Examples of such radicals include
fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,
fluoroethoxy, fluoropropoxy and cyclopropylmethoxy.
[0122] The term "aryl", when used alone or in combination, means a
carbocyclic aromatic moiety containing one, two or even three rings
wherein such rings may be attached together in a fused manner.
Every ring of an "aryl" multi-ring system need not be aromatic, and
the ring(s) fused to the aromatic ring may be partially or fully
unsaturated and include one or more heteroatoms selected from
nitrogen, oxygen and sulfur. Thus, the term "aryl" embraces
aromatic radicals such as phenyl, naphthyl, indenyl,
tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,
benzodioxazinyl, and the like. The "aryl" group may be substituted,
such as with 1 to 5 substituents including lower alkyl, hydroxyl,
halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the
like. Phenyl substituted with --O--CH.sub.2--O-- or
--O--CH.sub.2--CH.sub.2--O-- forms an aryl benzodioxolyl
substituent.
[0123] The term "carbocyclic", also referred to herein as
"cycloalkyl", when used alone or in combination, means a partially
or fully saturated ring moiety of carbon atoms containing one
("monocyclic"), two ("bicyclic") or even three ("tricyclic") rings
wherein such rings may be attached together in a fused manner and
formed from carbon atoms. Examples of saturated carbocyclic
radicals include saturated 3 to 6-membered monocyclic groups such
as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
[0124] The terms "ring" and "ring system" refer to a ring
comprising the delineated number of atoms, the atoms being carbon
or, where indicated, a heteroatom such as nitrogen, oxygen or
sulfur. Where the number of atoms is not delineated, such as a
"monocyclic ring system" or a "bicyclic ring system", the numbers
of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The
ring itself, as well as any substitutents thereon, may be attached
at any atom that allows a stable compound to be formed. The term
"nonaromatic" ring or ring system refers to the fact that at least
one, but not necessarily all, rings in a bicyclic or tricyclic ring
system is nonaromatic.
[0125] The term "cycloalkenyl", when used alone or in combination,
means a partially or fully saturated cycloalkyl containing one, two
or even three rings in a structure having at least one
carbon-carbon double bond in the structure. Examples of
cycloalkenyl groups include C.sub.3-C.sub.6 rings, such as
compounds including, without limitation, cyclopropene, cyclobutene,
cyclopentene and cyclohexene. The term also includes carbocyclic
groups having two or more carbon-carbon double bonds such as
"cycloalkyldienyl" compounds. Examples of cycloalkyldienyl groups
include, without limitation, cyclopentadiene and
cycloheptadiene.
[0126] The term "halo", when used alone or in combination, means
halogens such as fluorine, chlorine, bromine or iodine atoms.
[0127] The term "haloalkyl", when used alone or in combination,
embraces radicals wherein any one or more of the alkyl carbon atoms
is substituted with halo as defined above. For example, this term
includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such
as a perhaloalkyl. A monohaloalkyl radical, for example, may have
either an iodo, bromo, chloro or fluoro atom within the radical.
Dihalo and polyhaloalkyl radicals may have two or more of the same
halo atoms or a combination of different halo radicals. Examples of
haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl. "Perfluoroalkyl", as used herein, refers to
alkyl radicals having all hydrogen atoms replaced with fluoro
atoms. Examples include trifluoromethyl and pentafluoroethyl.
[0128] The term "heteroaryl", as used herein, either alone or in
combination, means a fully unsaturated (aromatic) ring moiety
formed from carbon atoms and having one or more heteroatoms
selected from nitrogen, oxygen and sulfur. The ring moiety or ring
system may contain one ("monocyclic"), two ("bicyclic") or even
three ("tricyclic") rings wherein such rings are attached together
in a fused manner. Every ring of a "heteroaryl" ring system need
not be aromatic, and the ring(s) fused thereto (to the
heteroaromatic ring) may be partially or fully saturated and
optionally include one or more heteroatoms selected from nitrogen,
oxygen and sulfur. The term "heteroaryl" does not include rings
having ring members of --O--O--, --S-- or --S--S--.
[0129] Examples of heteroaryl radicals, include unsaturated 5- to
6-membered heteromonocyclyl groups containing 1 to 4 nitrogen
atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3
-triazolyl] and tetrazole; unsaturated 7- to 10-membered
heterobicyclyl groups containing 1 to 4 nitrogen atoms, including
for example, quinolinyl, isoquinolinyl, quinazolinyl,
isoquinazolinyl, aza-quinazolinyl, and the like; unsaturated 5- to
6-membered heteromonocyclic group containing an oxygen atom, for
example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.; unsaturated 5
to 6-membered heteromonocyclic group containing a sulfur atom, for
example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated 5-
to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms
and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic
group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for
example, thiazolyl, isothiazolyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[0130] The term "heterocyclic", when used alone or in combination,
means a partially or fully saturated ring moiety containing one,
two or even three rings wherein such rings may be attached together
in a fused manner, formed from carbon atoms and including one or
more heteroatoms selected from N, O or S. Examples of saturated
heterocyclic radicals include saturated 3 to 6-membered
heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.
pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,
piperazinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of partially saturated heterocyclyl
radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and
dihydrothiazolyl.
[0131] The term "heterocycle" also embraces radicals where
heterocyclic radicals are fused/condensed with aryl radicals:
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,
benzoxadiazolyl]; unsaturated condensed heterocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
benzothiazolyl, benzothiadiazolyl]; and saturated, partially
unsaturated and unsaturated condensed heterocyclic group containing
1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,
2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples of
heterocyclic radicals include five to ten membered fused or unfused
radicals.
[0132] Examples of partially saturated and fully saturated
heterocyclyls include, without limitation, pyrrolidinyl,
imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl,
isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl,
chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihyrdo-1H-1.lamda.'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl and dihydrothiazolyl, and the like.
[0133] The phrase "a saturated or partially or fully unsaturated
3-8 membered monocyclic or a 6-12 membered bicyclic, said ring
system formed of carbon atoms optionally including 1-3 heteroatoms
if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms
selected from O, N, or S" as used herein is intended to encompass
all monocyclic and bicyclic rings as small as three atoms to as
large as 12 atoms in size, including both carbocyclic rings and
heterocyclic, aromatic and non-aromatic rings. The non-aromatic
rings may be partially or fully saturated in nature.
[0134] The term "alkylamino" includes "N-alkylamino" where amino
radicals are independently substituted with one alkyl radical.
Preferred alkylamino radicals are "lower alkylamino" radicals
having one to six carbon atoms. Even more preferred are lower
alkylamino radicals having one to three carbon atoms. Examples of
such lower alkylamino radicals include N-methylamino, and
N-ethylamino, N-propylamino, N-isopropylamino and the like.
[0135] The term "dialkylamino" includes "N,N-dialkylamino" and
--"N-di-C.sub..alpha.-.beta.-alkyl" where amino radicals are
independently substituted with two C.sub..alpha.-.beta.-alkyl
radicals. Preferred alkylamino radicals are "lower alkylamino"
radicals having one to six carbon atoms. Even more preferred are
lower alkylamino radicals having one to three carbon atoms. Example
of such lower alkylamino radicals include N,N-dimethylamino,
N,N-diethylamino, N-methyl,N-ethylamino and the like.
[0136] The term "oxo" is also used herein synonymously with
"carbonyl" and denotes --(C.dbd.O). The term "carbonyl" whether
used alone or with other terms, such as "aminocarbonyl", also
denotes --(C.dbd.O)--. "The term "aminocarbonyl" denotes an amide
group of the formula --C(.dbd.O)NH.sub.2.
[0137] The term "alkylthio" or "thioalkoxy" embraces radicals
containing a linear or branched alkyl radical, of one to ten carbon
atoms, attached to a divalent sulfur atom. An example of
"alkylthio" or "thioalkoxy" is methylthio,(CH.sub.3S--).
[0138] The term "Formula I" includes any sub formulas, such as
Formula II.
[0139] The term "pharmaceutically-acceptable" when used with
reference to a compound of Formulas I or II is intended to refer to
a form of the compound that is safe for administration. For
example, a salt form, a solvate, a hydrate or derivative form of a
compound of Formula I or of Formula II would be pharmaceutically
acceptable if it has been approved for mammalian use, via oral
ingestion or other routes of administration, by a governing body or
regulatory agency or authority, such as the Food and Drug
Administration (FDA) of the United States.
[0140] Included in the compounds of Formulas I and II are the
pharmaceutically acceptable salt forms of the free-base compounds.
The term "pharmaceutically-acceptable salts" embraces salts
commonly used to form alkali metal salts and to form addition salts
of free acids or free bases. As appreciated by those of ordinary
skill in the art, salts may be formed from ionic associations,
charge-charge interactions, covalent bonding, complexation,
coordination, etc. The nature of the salt is not critical, provided
that it is pharmaceutically acceptable.
[0141] Suitable pharmaceutically acceptable acid addition salts of
compounds of Formulas I and II may be prepared from an inorganic
acid or from an organic acid. Examples of such inorganic acids are
hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric,
carbonic, sulfuric and phosphoric acid. Appropriate organic acids
may be selected from aliphatic, cycloaliphatic, aromatic,
arylaliphatic, heterocyclic, carboxylic and sulfonic acids,
Examples of classes of suitable organic acids include, without
limitation, formic, acetic, adipic, butyric, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,
glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic,
embonic (pamoic), methanesulfonic, ethanesulfonic,
ethanedisulfonic, benzenesulfonic, pantothenic,
2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,
cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,
glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,
nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,
persulfuric, 2-phenylpropionic, picric, pivalic propionic,
succinic, thiocyanic, undecanoic, stearic, algenic,
.beta.-hydroxybutyric, salicylic, galactaric and galacturonic acid.
Suitable pharmaceutically-acceptable base addition salts of
compounds of Formulas I and II include metallic salts, such as
salts made from aluminum, calcium, lithium, magnesium, potassium,
sodium and zinc, or salts made from organic bases including,
without limitation, primary, secondary and tertiary amines,
substituted amines including cyclic amines, such as caffeine,
arginine, diethylamine, N-ethyl piperidine, histidine, glucamine,
isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine,
piperidine, triethylamine, disopropylethylamine and trimethylamine.
All of these salts may be prepared by conventional means from the
corresponding compound of the invention by reacting, for example,
the appropriate acid or base with the compound of Formulas
I-II.
[0142] Also, the basic nitrogen-containing groups can be quatemized
with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chloride, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain
halides such as decyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides, aralkyl halides like benzyl and phenethyl
bromides, and others. Water or oil-soluble or dispersible products
are thereby obtained.
[0143] Additional examples of such salts can be found in Berge et
al., J. Pharm. Sci., 66:1 (1977). Conventional methods may be used
to form the salts. For example, a phosphate salt of a compound of
the invention may be made by combining the desired compound free
base in a desired solvent, or combination of solvents, with
phosphoric acid in a desired stoichiometric amount, at a desired
temperature, typically under heat (depending upon the boiling point
of the solvent). The salt can be precipitated upon cooling (slow or
fast) and may crystallize (i.e., if crystalline in nature), as
appreciated by those of ordinary skill in the art. Further, hemi-,
mono-, di, tri- and poly-salt forms of the compounds of the present
invention are also contemplated herein. Similarly, hemi-, mono-,
di, tri- and poly-hydrated forms of the compounds, salts and
derivatives thereof, are also contemplated herein.
[0144] The term "derivative" is intended to encompass any salt of a
compound of this invention, any ester of a compound of this
invention, or any other compound, which upon administration to a
patient is capable of providing (directly or indirectly) a compound
of this invention, or a metabolite or residue thereof,
characterized by the ability to the ability to modulate an
enzyme.
[0145] The term "pharmaceutically-acceptable derivative" as used
herein, denotes a derivative which is pharmaceutically
acceptable.
[0146] The term "prodrug", as used herein, denotes a compound which
upon administration to a subject or patient is capable of providing
(directly or indirectly) a compound of this invention. Examples of
prodrugs would include esterified or hydroxylated compounds where
the ester or hydroxyl groups would cleave in vivo, such as in the
gut, to produce a compound according to Formula I-II. A
"pharmaceutically-acceptable prodrug" as used herein, denotes a
prodrug which is pharmaceutically acceptable. Pharmaceutically
acceptable modifications to the compounds of Formula I-II are
readily appreciated by those of ordinary skill in the art.
[0147] The compound(s) of Formulas I or II may be used to treat a
subject by administering the compound(s) as a pharmaceutical
composition. To this end, the compound(s) can be combined with one
or more excipients, including without limitation, carriers,
diluents or adjuvants, to form a suitable composition, which is
described in more detail herein.
[0148] The term "excipient", as used herein, denotes any
pharmaceutically acceptable additive, carrier, adjuvant, or other
suitable ingredient, other than the active pharmaceutical
ingredient (API), which is typically included for formulation
and/or administration purposes. "Diluent" and "adjuvant" are
defined hereinafter.
[0149] The terms "treat", "treating," "treatment," and "therapy" as
used herein refer to therapy, including without limitation,
curative therapy, prophylactic therapy, and preventative therapy.
Prophylactic treatment generally constitutes either preventing the
onset of disorders altogether or delaying the onset of a
pre-clinically evident stage of disorders in individuals.
[0150] The phrase "effective dosage amount" is intended to quantify
the amount of each agent, which will achieve the goal of
improvement in disorder severity and the frequency of incidence
over treatment of each agent by itself, while avoiding adverse side
effects typically associated with alternative therapies.
Accordingly, this term is not limited to a single dose, but may
comprise multiple dosages required to bring about a therapeutic or
prophylactic response in the subject. For example, "effective
dosage amount" is not limited to a single capsule or tablet, but
may include more than one capsule or tablet, which is the dose
prescribed by a qualified physician or medical care giver to the
subject.
[0151] The term "leaving group" (also denoted as "LG") generally
refers to groups that are displaceable by a nucleophile. Such
leaving groups are known in the art. Examples of leaving groups
include, but are not limited to, halides (e.g., I, Br, F, Cl),
sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH.sub.3),
N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
Nucleophiles are species that are capable of attacking a molecule
at the point of attachment of the leaving group causing
displacement of the leaving group. Nucleophiles are known in the
art. Examples of nucleophilic groups include, but are not limited
to, amines, thiols, alcohols, Grignard reagents, anionic species
(e.g., alkoxides, amides, carbanions) and the like.
General Synthetic Procedures
[0152] The present invention further comprises procedures for the
preparation of compounds of Formulas I and II. The compounds of
Formulas I or II can be synthesized according to the procedures
described in the following Schemes 1-9, wherein the substituents
are as defined for Formulas I and II above, except where further
noted. The synthetic methods described below are merely exemplary,
and the compounds of the invention may also be synthesized by
alternate routes utilizing alternative synthetic strategies, as
appreciated by persons of ordinary skill in the art.
[0153] The following list of abbreviations used throughout the
specification represent the following and should assist in
understanding the invention: [0154] ACN, MeCN--acetonitrile [0155]
Aq., aq.--aqueous [0156] Ar--argon (gas) [0157]
BOP--benzotriazol-1-yl-oxy [0158] Hexafluorophosphate [0159]
BuLi--Butyllithium [0160] Cs.sub.2CO.sub.3--cesium carbonate [0161]
CHCl.sub.3--chloroform [0162] CH.sub.2Cl.sub.2,
DCM--dichloromethane, methylene chloride [0163] Cu(1)I--copper(1)
iodide [0164] DCC--dicyclohexylcarbodiimide [0165]
DIC--1,3-diisopropylcarbodiimide [0166] DIEA,
DIPEA--diisopropylethylamine [0167] DME--dimethoxyethane [0168]
DMF--dimethylformamide [0169] DMAP--4-dimethylaminopyridine [0170]
DMS--dimethylsulfide [0171] DMSO--dimethylsulfoxide [0172] EDC,
EDCI--1-(3-dimethylaminopropyl)-3-ethylcarbodiimide [0173]
Et.sub.2O--diethyl ether [0174] EtOAc--ethyl acetate [0175]
FBS--fetal bovine serum [0176] G,gm--gram [0177] h,hr--hour [0178]
H.sub.2--hydrogen [0179] H.sub.2O --water [0180]
HATU--O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoropho-
sphate [0181] HBr--hydrobromic acid [0182] HCl--hydrochloric acid
[0183] HOBt--1-hydroxybenzotriazole hydrate [0184] HOAc--acetic
acid [0185] HPLC--high pressure liquid chromatography [0186] IPA,
IpOH--isopropyl alcohol [0187] K.sub.2CO.sub.3--potassium carbonate
[0188] KI--potassium iodide [0189] LG--leaving group [0190]
LDA--Lithium diisopropylamide [0191] LiOH--lithium hydroxide [0192]
MgSO.sub.4--magnesium sulfate [0193] MS--mass spectrum [0194]
MeOH--methanol [0195] N.sub.2--nitrogen [0196] NaCNBH.sub.3--sodium
cyanoborohydride [0197] Na.sub.2CO.sub.3--sodium carbonate [0198]
NaHCO.sub.3--sodium bicarbonate [0199] NaH--sodium hydride [0200]
NaI--sodium iodide [0201] NaBH.sub.4--sodium borohydride [0202]
NaOH--sodium hydroxide [0203] Na.sub.2SO.sub.4--sodium sulfate
[0204] NH.sub.4Cl--ammonium chloride [0205] NH.sub.4OH--ammonium
hydroxide [0206] P(t-bu).sub.3--tri(tert-butyl)phosphine [0207]
PBS--phospate buffered saline [0208] Pd/C--palladium on carbon
[0209] Pd(PPh.sub.3).sub.4--palladium(0)triphenylphosphine tetrakis
[0210]
Pd(dppf)Cl.sub.2--palladium(1,1-bisdiphenylphosphinoferrocene)II
chloride [0211] Pd(PhCN).sub.2Cl.sub.2--palladium di-cyanophenyl
dichloride [0212] Pd(OAc).sub.2--palladium acetate [0213]
Pd.sub.2(dba).sub.3--tris(dibenzylideneacetone)dipalladium [0214]
PyBop--benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium [0215]
hexafluorophosphate [0216] RT, rt--room temperature [0217] RBF,
rbf--round bottom flask [0218] TLC, tlc--thin layer chromatography
[0219] TBAF--Tetrabutylammonium flouride [0220]
TBTU--O-benzotriazol-1-yl-N,N,N,N'-tetramethyluronium [0221]
tetrafluoroborate [0222] TEA, Et.sub.3N--triethylamine [0223]
TFA--trifluoroacetic acid [0224] THF--tetrahydrofuran [0225]
UV--ultraviolet light
[0226] While the synthetic strategy for preparing the compounds of
Formulas I and II may vary, as appreciated by persons skilled in
the art, one strategy for devising a method of making compounds of
these formulas is by retro-synthetic disconnection. For
example,
##STR00006##
as shown in Formulas I-II above, each squiggly line represents a
possible point of bond-construction, whose order is generally
dependent upon the particular compound being synthesized. Such bond
construction methods are generally described in synthetic Schemes
1-9 below.
##STR00007##
[0227] Amine intermediate 4 can be prepared according to the method
generally described in Scheme 1. As shown, spiro-substituted- or
gem-dialky-substituted (not shown) oxo-R.sup.5 ring intermediates 1
can be converted directly to the amino-intermediate 4 using known
reductive amination methods, such as in the presence of sodium
cyanoborohydride and ammonium acetate. Alternatively, the carbonyl
of compound 1 may be reduced to the corresponding alcohol 2 using
conventional reducing reagents, and then displaced to form the
corresponding azido-intermediate 3 using known reagents, such as
DPPA, in the presence of a suitable base as shown. Intermediate 3
may be reduced with a suitable reducing agent or by known methods,
including triphenylphosphene, trimethylphosphene or lithium
aluminum hydride (LAH), to produce the desired amino adduct 4.
[0228] Yet another method of forming the amine adduct 4, can be via
an imine formation to form compound 5. The imine double bond of
compound 5 may then be successively reduced and hydrolyzed to yield
the primary amine product 4. Such steps may be conducted using
known, convention methods, as appreciated by those skilled in the
art.
##STR00008##
[0229] Alternatively, amine intermediates 4 may be prepared by the
method shown in scheme 2 above. Desirably substituted compounds 4a
may first be treated with a strong base, such as LDA or n-butyl
lithium, to form an anion that may then be added to a sufinylimine
intermediate 4b to form the corresponding coupled adduct 4c. Open
intermediate 4c may subsequently be treated with a strong base,
such as NaH (wherein, e.g., X is a nucleophile such as OH, SH or
NHR.sup.6 or TBAF (wherein, e.g., X1 is OSiR.sub.3) to form
intermediate 6. Intermediate 6 may then be deprotected to provide
the desired spiro amine compound 4.
##STR00009##
[0230] Amine intermediate 4 can also be prepared from other amine 4
precursors such as 4d containing an appropriate leaving group (LG,
e.g., Cl, Br, I, OTf, etc) as shown in scheme 3 above. Using this
method, compound 4d, with the amino group used as is,
mono-protected (compound 4e), or doubly protected (compound 4f
having PG1 and PG2 protecting groups as shown), can be coupled with
the requisite neucleophilic reagents with a catalyst such as a
Pd-catalyst selected from appropriate sources. The said
neucleophilic reagents can be selected from, but not limited to,
commercial or pre-formed boronic reagents, stannane reagents, Zinc-
or Magnesium-derived metallic reagents. After deprotection if
necessary, amine intermediate 4 can be obtained.
##STR00010## ##STR00011##
[0231] Scheme 4 describes, generally, multiple different methods
for constructing the bond between the propyl backbone starting
material or intermediate 6' (sub-scheme 1) or 6 (sub-scheme 2) and
an spiro ring intermediate 4, thereby synthesizing a desired
intermediate 8' or a final compound 8 of Formulas I-II. One method
to make this bond is to react an epoxide intermediate 6 or 6'
(Note: the epoxide 6 or 6' may be purchased commercially or made
via known, published methods such as from the olefin precursor),
with an amino-spiro intermediate 4, as shown. The reaction may
proceed in the presence of a polar solvent, such as an alcohol or
dioxanes, and may require additional reagents, as appreciated by
those skilled in the art. Additionally, the reaction may require
heat for a period of time. Note that while the scheme described the
addition of heat, this is by way of example, and not every reaction
would require heat as appreciated by those of ordinary skill in the
art. The protecting group may be removed using an acid, such as
HCl, such that the bonded adduct 8' is recovered as an HCl
salt.
[0232] Alternatively, desired intermediates 8' may be synthesized
starting with an amine-protected aldehyde intermediate 7'
(sub-scheme 3) or 7 (sub-scheme 4) and condensing the aldehyde with
a primary or secondary amine 4 to form an imine (not shown,
generally formed in-situ and not isolated). The imine can then be
reduced using a known reducing agent, such as a hydride or
borohydride, the reduced intermediate may be deprotected to provide
an intermediate 8' having an amine useful to prepare compounds 8 of
Formulas I-II.
##STR00012##
[0233] Scheme 5 describes, generally, another method for
constructing gem-dialkyl (not shown) or spiro (shown) compounds 4
in schemes 2 and 3 above, by first preparing the corresponding
bromo-keto-intermediate 14 as schematically illustrated above. As
shown, a methoxy picolinic acid 9 can be reacted with an aqueous
bromine source, such bromine, in the presence of a suitable
solvent, such as DCM/water, to form the corresponding brominated
intermediate 10. The acid group of compound 10 can be converted to
the corresponding Weinreb amide under known conditions, such as
using EDC-HCl in the presence of HOBt, a base such as TEA, and a
suitable solvent such as DCM. Weinreb 11 may be treated with a
desired Grignard reagent, such as vinylmagnesium bromide as shown
above, in the presence of a suitable solvent, such as THF, to form
the allylic ketone species 12. Alternatively, the Weinreb amide
species may be bypassed by treating compounds 10 directly with the
Grignard reagents, such the one shown above, to afford compounds
12. Compound 12 can undergo a Grubb's metathesis, such as by
utilizing exo-methylene cyclobutane as shown above, to form
intermediate 13, which may then be cyclized to ring closure using a
suitable acidic environment, such as in EtOH/HCl, to provide the
desired compounds 14. An additional method to prepare
mono-substituted aza-chroman compounds, but not gem-dialkyl or
spiro aza-chroman compounds 14 is described in Sarges et at, J. Med
Chem., 1990, 33, 1859-1865, which disclosure is hereby incorporated
herein by reference in its entirety. The keto-intermediate 14 can
then be converted to the corresponding primay amino species using
the chemistry taught herein.
##STR00013##
[0234] Scheme 6 describes, generally, yet another method for
constructing gem-dialkyl (not shown) or spiro (shown) intermediates
13 in scheme 5 above. Compound 13 in turn may be converted to the
desired bromo-keto-intermediate 14 as schematically illustrated
above. As shown, brominated intermediate 10 from scheme 5 can be
reacted with an acid, such as sulfuric acid as shown, in a protic
solvent, such as MeOH, to form the corresponding methyl ester
intermediate 15. The ester group of compound 15 can be converted to
the corresponding phosphonate ester under Horner-Emmons type
conditions, which are known in the art, such as using a phosphonate
species in the presence of a strong base, such as LiHMDS as shown,
and a suitable solvent such as THF and toluene. The resulting
phosphonate adduct 16 may be deprotonated with a strong base, such
as with liOMe in the presence of an alcoholic solvent such as MeOH
and/or I-PrOH, and the lithium enolate can then be reacted with
cyclobutanone to afford the adduct compound 13 in high yield.
Intermediate 13 may then be cyclized to ring closure using suitable
conditions, such as those shown above in scheme 6, to provide the
desired compounds 14. Additional description of useful methods
which may be used to prepare compounds similar to compound 14 are
described in general in Harada et at, JP patent application No.
08099982A , Yasuda et al, J. Org. Chem. 2004, 69, pg 1958, Yazbeck
et al, Org. Process Res. Dev. 2006, 10, pg 655, and in Keneko et
al, Chem. Pharm. Bull., 2004, 52, pg 675, which disclosures are
hereby incorporated herein by reference in its entirety. The
keto-intermediate 14 can then be converted to the corresponding
primay amino species using the chemistry taught herein.
[0235] It should be appreciated that schemes 5 and 6 illustrate
exemplary methods for preparing the right-side spiro or gem-dialkyl
pieces of compounds of Formulas I and II. Reaction yields for each
step in schemes 5 and 6 range from about 50% to 90+%. Accordingly,
these methods may provide a more efficient process for preparing
desired intermediates 14. Further, utilizing these methods may
afford other spirocyclic rings of differeing sizes and heteroatoms,
encompassed in the compounds of the present invention.
##STR00014##
[0236] Scheme 7 illustrates how one may construct the R.sup.1 to
amine-backbone bond, where R.sup.1, as shown, is an aromatic
moiety. Intermediate 8' can be heated in a microwave oven with a
desirably substituted chloro-substituted aromatic compound 18 in
the presence of a suitable base, such as diisopropylethylamine
(DIEA) in a suitable solvent, such as isopropyl alcohol (IPA) to
afford the desired product compound 19 of Formula I or II.
##STR00015##
[0237] Scheme 8 illustrates an alternative method of constructing
the R.sup.1 to amine backbone bond, where R.sup.1, as shown, is
another aromatic moiety. Intermediate 20 can be heated together
with an iodo-fluorophenyl compound 21 in the presence of Copper
iodide (CuI), a suitable base such as potassium phosphate, and a
suitable solvent or combination of solvents, such as ethylene
glycol and IPA, for a suitable time period to afford the desired
product compound 22 of Formula I or II.
##STR00016##
[0238] Scheme 9 illustrates yet another alternative method of
constructing the R.sup.1 to amine backbone bond, where R.sup.1, as
shown, is an aromatic moiety. Intermediate 20 can be combined with
suitable amounts of potassium 2-methylpropan-2-olate in toluene and
stirred at RT. To this mixture is added 2-iodopyrazine 23 and
BINAP, followed by palladium (II) acetate and the mixture is heated
to about 50.degree. C. for a suitable time period in which to
afford the desired compound 24. The reaction mixture is then cooled
and compound 24 can be purified from this mixture using known
conventional methods, such as column chromatography or HPLC
methods.
[0239] To enhance the understanding and appreciation of the present
invention, the following specific examples (starting reagents,
intermediates and compounds of Formulas I-II) are set forth. The
following analytical methods were used to purify and/or
characterize the compounds, and intermediates, described in the
examples below. Additional general and specific exemplary methods
for making the intermediates and building block compounds are
described in PCT publication No. WO 2007061670, which disclosure is
incorporated herein by reference in its entirety.
Analytical HPLC and LC-MS Methods:
[0240] Unless otherwise indicated, all analytical HPLC analyses
were run on an Agilent Model 1100 series system LC/MSD SL using one
of the two following Columns: (a) Phenomenex Sernegi (4 micron,
C18, 50.times.2 mm) or (b) a Gemini column (5 micron, C18,
100.times.2 mm). A typical run through the instrument included:
eluting at 1 ml/min with an linear gradient of 10% (v/v) to 100%
MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 minutes; conditions
may be varied to achieve optimal separation.
[0241] Chromatography: Unless otherwise indicated, crude
product-containing residues were purified by passing the crude
material orconcentrate through an ISCO brand silica gel column
(pre-packed or individually packed with SiO.sub.2) and eluting the
product off the column with a solvent gradient as indicated. For
example a description of (330 g SiO.sub.2, 0-40% EtOAc/Hexane)
means the product was obtained by elution from the column packed
with 330 gms of silica, with a solvent gradient of 0% to 40% EtOAc
in Hexanes.
Preparative IPLC Method:
[0242] Unless otherwise indicated, the compounds described herein
were purified via reverse phase HPLC using one of the following
instruments: Shimadzu, varian, Gilson; utilizing one of the
following two HPLC columns: (a) a Phenomenex Luna or (b) a Gemini
column (5 micron or 10 micron, C18, 150.times.50 mm)
[0243] A typical run through the instrument included: eluting at 45
ml/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v
TFA) in water (0.1% TFA) over 10 minutes; conditions can be varied
to achieve optimal separations.
Proton NMR Spectra:
[0244] Unless otherwise indicated, all .sup.1H NMR spectra were run
on a Bruker series 300 MHz instrument or a Bruker series 400 MHz
instrument. Where so characterized, all observed protons are
reported as parts-per-million (ppm) downfield from
tetramethylsilane (TMS) or other internal reference in the
appropriate solvent indicated.
Mass Spectra (MS)
[0245] Unless otherwise indicated, all mass spectral data for
starting materials, intermediates and/or exemplary compounds are
reported as mass/charge (m/z), having an (M+H.sup.+) molecular ion.
The molecular ion reported was obtained by electrospray detection
method (commonly referred to as an ESI MS) utilizing a PE SCIEX API
150EX MS instrument. Compounds having an isotopic atom, such as
bromine and the like, are generally reported according to the
detected isotopic pattern, as appreciated by those skilled in the
art.
Naming Convention
[0246] The compounds disclosed and described herein have been named
using the naming convention provided with Chem-Draw Ultra 8.0
software, available in Chem Office. In some instances, compounds
were named with the term "spirocarbocycle" inserted where
appropriate. For example, where the chroman is substituted with
2,2-spirocyclobutyl, "2,2-spirocyclobutyl" is added to the
Chem-Draw nomenclature in the appropriate place. Chem-Draw utilizes
the ISIS Draw software compound naming convention, as appreciated
by those skilled in the art.
EXAMPLES
[0247] The Examples, described herein below, represent various
exemplary starting materials, intermediates and compounds of
Formulas I-II, which should assist in a better understanding and
appreciation of the scope of the present invention and of the
various methods which may be used to synthesize compounds of
Formulas I and II. It should be appreciated that the general
methods above and specific examples below are illustrative only,
for the purpose of assistance and of understanding the present
invention, and should not be construed as limiting the scope of the
present invention in any manner.
Example 1
##STR00017##
[0248]
(4S,5S)-tert-Butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-(trifluorome-
thyl)pyridin-4-yl) methyl)oxazolidine-3-carboxylate
Step 1:
(S)-Methyl2-(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyridin-4--
yl)propanoate
[0249] The title compound was prepared according to previously
reported procedure (U.S. patent application Ser. No. 11/575,187)
from (R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate and
4-iodo-2-(trifluoromethyl)pyridine (this starting material was
prepared according to a procedure described in Eur. J. Org. Chem.
2003, 1559-1568).
Step
2:(4S,5S)-tert-Butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-(trifluorome-
thyl)pyridin-4-yl)methyl)oxazolidine-3-carboxylate
[0250] The title compound was prepared according to procedure
described in U.S. patent application Ser. No. 11/575,187, from
(S)-methyl2-(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyridin-4-yl)prop-
anoate.
Example 2
##STR00018##
[0251]
(S)-tert-Butyl3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-
-2-yl)propan-2-ylcarbamate
Step 1:
(S)-tert-Butyl3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazo-
l-2-yl)propan-2-2-ylcarbamate
[0252] A solution of 2-bromothiazole (3 ml, 37 mmol) in ether (75
mL) was cooled to -78.degree. C. and treated with n-butyllithium 2M
in hexanes (18 ml, 37 mmol). After stirring the reaction for 30
minutes, a solution of
(S)-methyl2-(tert-butoxycarbonyl)-3-(7-chlorobenzo[d][3]dioxol-5-yl)pr-
opanoate (6.610 g, 18 mmol) in ether (75 mL) was added, and the
reaction mixture was allowed to stir at -78.degree. C. for 1 hour.
The reaction mixture was quenched with saturated NH4CI solution,
washed with water and brine. The organic layers were dried over
MgSO.sub.4 and concentrated under reduced pressure. Purification of
the crude residue by column chromatography gave
(S)-tert-butyl3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)-
propan-2-ylcarbamate (4.22 g, 56% yield) as a yellow oil.
Step 2:
tert-Butyl(1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-
-(thiazol-2-yl)propan-2-ylcarbamate
[0253] A cooled solution (0.degree. C.) of
(S)-tert-butyl3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)-
propan-2-ylcarbamate (4.220 g, 10 mmol) in EtOH (60 mL) was added
dropwise via cannula to a cooled solution (-78.degree. C.) of
lithium tri-tert-butoxyaluminum hydride 1M in THF (21 ml, 21 mmol)
in EtOH (40 mL). After stirring for 2 hours, the reaction mixture
was quenched with 1N HCl and diluted with EtOAc. The organic layer
was washed with water, saturated NaHCO.sub.3 solution, and brine.
The organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude residue was crystalized from hot
EtOH/water and the solid was collected yielding
tert-butyl(1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiaz-
ol-2-yl)propan-2-ylcarbamate (3.250 g, 77% yield) as a white
solid.
Step 3:
tert-Butyl(1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[-
d][1,3]dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate
[0254] A suspension of
tert-butyl(1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiaz-
ol-2-yl)propan-2-ylcarbamate (3.250 g, 8 mmol) in DCM (24 mL) was
treated with 2,6-lutidine (1 ml, 12 mmol) followed by
tert-butyldimethylsilyl triflate (2 ml, 9 mmol) and was allowed to
stir at RT for 2 hours. An additional equivalent of TBS triflate
was added followed by an additional equivalent of base. After 1
hour, DIEA (2 ml, 12 mmol) was added, followed by
di-tert-butyldicarbonate 1M in THF (8 ml, 8 mmol), and the reaction
mixture was allowed to stir at RT overnight. The reaction mixture
was quenched with 2N HCl solution, diluted with DCM, and washed
with saturated NaHCO.sub.3 solution and brine. The organics were
dried over MgSO.sub.4 and concentrated under reduced pressure.
Purification of the crude residue by column chromatography gave
tert-butyl(1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]-
dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate (1.850 g, 45%
yield).
Step 4:
tert-Butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(7-chlorobenzo[-
d][1,3]dioxol-5-yl)-4-oxobutan-2-ylcarbamate
[0255] A solution
tert-butyl(1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]-
dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate (1.85 g, 3.51
mmol) in MeCN (14 mL) was treated with 4A mol. seives and was
allowed to stir at RT for 10 minutes. Methyl
trifluoromethanesulfonate (0.464 ml, 4.21 mmol) was added, and the
reaction mixture was allowed to stir for 30 minutes. The reaction
mixture was then concentrated under reduced pressure,and the crude
residual material was dissolved in MeOH (14 mL), and cooled to
0.degree. C. The mixture was then treated with sodium borohydride
(0.398 g, 10.5 mmol) and allowed to warm to RT and stir for an
additional 20 minutes. The reaction mixture was diluted with EtOAc,
filtered through celite and concentrated under reduced pressure.
The residue was dissolved in MeCN (10 mL) and water (4 mL) and was
treated with mercury (II) chloride (0.953 g, 3.51 mmol). After
stirring for 30 minutes the reaction mixture was diluted with ether
and filtered through a short plug of silica. The filtrate was then
concentrated under reduced pressure and the crude residue was
purified by column chromatography yielding
tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(7-chlorobenzo[d][1,3]-
dioxol-5-yl)-4-oxobutan-2-ylcarbamate.
Example 3
##STR00019##
[0256]
tert-Butyl(2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3-(tert-butyldimethy-
lsilyloxy)-4-hydroxybutan-2-ylcarbamate
Step 1:
N-((2S,3S)-1-(benzo[d][1,3]dioxol-4-yl)-3,4-bis(tert-butyldimethyl-
silyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide
[0257] To a slurry of magnesium turnings (1.09 g, 44.8 mmol) in 5
mL of THF was added iodine (0.0650 g, 0.256 mmol), followed by a
solution of 5-(chloromethyl)benzo[d][1,3]dioxole (6.55 g, 38.4
mmol) in 30 mL of THF. After 1 minute, the exothermic reaction
mixture was placed in an ice bath for 1 minute and then stirred at
ambient temperature for 1 hour. TMEDA (7.68 ml, 51.2 mmol) was
added to the reaction and the mixture was cooled to -78.degree. C.
for 5 minutes at which point a solution of
(E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropan-
e-2-sulfinamide (5400 mg, 12.8 mmol) in 25 mL THF was added via a
syring pump over 15 minutes. The reaction was allowed to warm to RT
over the course of 2 hours then stirerd at RT for an additional
hour. The mixture was diluted with ethyl acetate (100 mL) and
poured in saturated ammonium chloride (250 mL). The aqueous layer
was extracted with ethyl acetate (2.times.250 mL) and the combined
organic layers were washed with water and then brine and dried over
Na.sub.2SO.sub.4. The organic colvents were filtered, concentrated
under reduced pressure and the crude material was purified by
silica gel to provide
N-((2R,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3,4-bis(tert-butyldimethylsilylox-
y)butan-2-yl)-2-methylpropane-2-sulfinamide (4.51 g, 63.1% yield)
as a colorless oil.
Step 2:
tert-Butyl(2S,3S)-1-(benzo[d][1,3]dioxol-4-yl)-3-(tert-butyldimeth-
ylsilyloxy)-4-hydroxybutan-2-ylcarbamate
[0258] To a solution of
N-((2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3,4-bis(tert-butyldimethylsilylox-
y)buta-2-yl)-2-methylpropane-2-sulfinamide (2300 mg, 4 mmol) in 25
mL of ethanol at 0.degree. C. was added 4M HCl in dioxane (6 ml, 25
mmol). After stirring at 0.degree. C. for a total of 7 hours, TEA
(4 ml, 29 mmol) was added dropwise followed by addition of 25 mL of
DCM and di-tert-butyl dicarbonate (2 g, 9 mmol). The mixture was
stirred at rt for 48 hours, then diluted with DCM (50 mL) and
poured in saturated ammonium chloride (250 mL). The aqueous layer
was extracted with DCM (4.times.100 mL). The combined organic
layers were washed with water and brine and dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure,
to provide an oil that was flashed through a plug of silica gel to
provide
tert-butyl(2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3-(tert-butyldimethylsilyl-
oxy)-4-hydroxybutan-2-ylcarbamate as a colorless oil.
Example 4
##STR00020##
[0259]
(4S,5S)-tert-Butyl4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)--
5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate
Step 1:
(S)-Methyl2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]diox-
ol-5-yl) propanoate
[0260] To a 25 mL RBF was added zinc powder (1.03 g, 15.8 mmol) and
iodine (0.0161 g, 0.0633 mmol). The mixture was heated with a heat
gun for 5 minutes and the resulting mixture was then flushed with
nitrogen 3 times and allowed to cool to rt. A solution of
(R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate (3.47 g, 10.5
mmol) in 5 mL of DMF was added dropwise to the mixture over 3
minutes and the resulting grey slurry was stirred at 0.degree. C.
for 20 minutes before being warmed to rt. After stirring at rt for
30 minutes, 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (2.50 g, 10.5
mmol), Pd.sub.2(dba).sub.3 (0.193 g, 0.211 mmol) and S(Phos) (0.346
g, 0.844 mmol) were added and the reaction mixture was heated to
40.degree. C. for 2 hours. The resulting mixture was cooled to rt
and partitioned between ethyl acetate (50 mL) and a solution of
.about.9:1 saturated ammonium chloride/ammonium hydroxide pH=9 (250
mL). The aqueous layer was extracted with ethyl acetate
(3.times.100 mL) and the combined organic layers were washed with
water, brine, and dried over sodium sulfate. Concentration of the
filtered solvents and purification of resulting crude material by
silica gel chromatography provided (S)-methyl
2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoat-
e (1.89 g, 49.9% yield) as a slightly brown oil.
Step 2:
(S)-2-(tert-Butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-y-
l)propanoic acid
[0261] To a solution of
(S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl-
) propanoate (1850 mg, 5 mmol) in 50 mL of THF at 0.degree. C. was
added LiOH (0.2 M, 26 ml, 5 mmol) over 10 minutes. The reaction was
stirred for 2 hours and was then washed with ether (200 mL),
acidified to pH 4 with 2 N HCl and extracted with ethyl acetate
(4.times.100 mL). The organics were washed with water and brine and
dried over sodium sulfate. Concentration provided
(S)-2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propa-
noic acid (1.75 g, 98% yield) as a colorless oil.
Step 3:
(S)-3-(tert-Butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-y-
l)-2-oxobutyl acetate
[0262] To a solution of
(S)-2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
propanoic acid (1650 mg, 5 mmol) in 50 mL of THF at 0.degree. C.
was added TEA (0.7 ml, 5 mmol) and isobutyl chloroformate (0.6 ml,
5 mmol). The reaction mixture was stirred at 0.degree. C. for 1.5
hours then filtered through a frit containing celite. The solution
was cooled to 0.degree. C. and treated with freshly prepared
diazomethane (0.5 M in ether, 14 ml, 7 mmol). After stirring for 1
hour at 0.degree. C. the reaction was poured into saturated sodium
bicarbonate 250 mL and the aqueous layer was extracted with ethyl
acetate (3.times.100 mL). The combined organic layers were washed
with water and then brine and dried over Na.sub.2SO.sub.4.
Concentration of solvents under reduced pressure provided the diazo
ketone as a yellow solid that was carried on without further
purification. The derived diazo ketone was taken up in 50 mL of THF
and cooled to 0.degree. C. at which point hydrobromic acid, 33 wt.
% in acetic acid (0.7 ml, 12 mmol) was added dropwise over 1
minute. After stirring at 0.degree. C. for 1 hour potassium
carbonate (1.0 g, 7 mmol) and sodium acetate (4 g, 48 mmol) were
added to the mixture. The THF was removed in vacuo and 15 mL of DMF
was added to the reaction. The resulting slurry was stirred for 10
minutes at which point the reaction mixture was diluted with ethyl
acetate (50 mL) and poured in water 100 mL. The aqueous layer was
extracted with ethyl acetate (2.times.100 mL). The combined organic
layers were washed with water and then brine and dried over
Na.sub.2SO.sub.4. Concentration of the solvents under reduced
provided
(S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-
-yl)-2-oxobutyl acetate (1.10 g, 57% yield) as a white solid.
Step 4: (2S,
3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-hy-
droxybutyl acetate
[0263] A solution of
(S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-ox-
obutyl acetate (1100 mg, 2741 .mu.mol) in 45 mL of ethanol cooled
to 0.degree. C. was added to lithium aluminumtri-tert-butoxyhydride
(1 M in THF, 5481 .mu.l, 5481 .mu.mol) in 15 mL of ethanol at
-78.degree. C. dropwise via cannula over 5 minutes. After stirring
at -78.degree. C. for 2 hours the reaction was quenched with 10 mL
of 1 N HCl and the mixture was diluted with ethyl acetate (500 mL).
The reaction was poured into 200 mL of water, the layers were
separated and the aqueous layer was extracted with ethyl acetate
(3.times.100 mL). The combined organics were washed with water,
brine, and dried over sodium sulfate, filtered and concentrated to
provide
(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)--
2-hydroxybutyl acetate (1060 mg, 96% yield) as a white solid.
Step 5:
(4S,5S)-tert-butyl4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-
-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate
[0264] To a solution of
(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)--
2-hydroxybutyl acetate (1050 mg, 2603 .mu.mol) in 5 mL of DMF was
added 2-methoxypropene (872 .mu.l, 9111 .mu.mol) and CSA (181 mg,
781 .mu.mol). The mixture was stirred at rt overnight, and 91 mg of
CSA and 0.872 mL of 2-methoxypropene were added. The reaction was
stirred for 2 hours, then poured into ice-cold aqueous saturated
sodium bicarbonate (150 mL) and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
water, brine, and dried over sodium sulfate. The derived yellow oil
was taken up in 10 mL of methanol cooled to 0.degree. C. and
treated with potassium carbonate (1079 mg, 7809 .mu.mol). After
warming to rt over the course of 1 hour the reaction was diluted
with ethyl acetate (25 mL) and poured in saturated ammonium
chloride (50 mL). The aqueous layer was extracted with ethyl
acetate (3.times.50 mL) and the combined organic layers were washed
with water and then brine and dried over Na.sub.2SO.sub.4.
Concentration of the solvents under reduced pressure and
purification by silica gel provided
(4S,5S)-tert-butyl4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-(hyd-
roxymethyl)-2,2-dimethyloxazolidine-3-carboxylate as a colorless
oil.
Example 5
##STR00021##
[0265]
(4S,5S)-tert-Butyl4((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-5-
-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate
Step 1:
(Z)-Methyl2-(tert-butoxycarbonyl)-3-(2-methylbenzo[d][1,3]dioxol-5-
-yl)acrylate
[0266] To a solution of
methyl2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (5255
mg, 17678 .mu.mol) in 25 mL of DCM at 0.degree. C. was added DBU
(2665 .mu.l, 17678 .mu.mol) dropwise. To the mixture was then added
a solution of 2,2-dimethylbenzo[d][1,3]dioxole-5-carbaldehyde (3000
mg, 16836 .mu.mol) in 10 mL of DCM over 5 minutes so as to maintain
internal temperature below 10.degree. C. The reaction was warmed to
rt and stirred overnight before being diluted with DCM (25 mL) and
poured in saturated ammonium chloride (100 mL). The aqueous layer
was extracted with DCM (1.times.50 mL). The combined organic layers
were washed with 10% aqueous sodium bicarbonate then water then
brine and dried over Na.sub.2SO.sub.4. Concentration under reduced
pressure and purification by silica gel provided
(Z)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]di-
oxol-5-yl)acrylate (5005 mg, 85.1% yield) as a white solid.
Step 2:
(S)-Methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]diox-
ol-5-yl) propanoate
[0267] To a slurry of
(Z)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl-
) acrylate (5000 mg, 14311 .mu.mol) in 30 mL of MeOH was added
[Rh(duanphos)cod]BF.sub.4 (101.1 mg, 143.1 .mu.mol) followed by an
additional 15 mL of methanol. The mixture was purged with hydrogen
3 times and then sealed at 50 psi of H.sub.2. After 3 hours
reaction the reaction was concentrated and purified by silica gel
chromatography to provide
(S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dio-
xol-5-yl)propanoate (5000 mg, 99.43% yield) as a colorless oil.
Step 3:
(S)-2-(tert-Butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-y-
l)propanoic acid
[0268] To a solution of
(S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl-
)propanoate (5000 mg, 14229 .mu.mol) in 100 mL of THF at 0.degree.
C. was added lithium hydroxide (0.2 M, 28458 .mu.l, 14229 .mu.mol)
over 10 minutes. After stirring at 0.degree. C. for 1 hour the
reaction was poured into a separatory funnel and 100 mL of water
was added. The mixture was washed with 150 mL of ether, then
acidified to pH 2-3- with 1 N HCl. Ethyl acetate was added, the
layers were separated and the aqueous layer was extracted with
ethyl acetate (3.times.100 mL). The combined organics were washed
with water and then brine before being dried over sodium sulfate,
filtered and concentrated to furnish
(S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propa-
noic acid (4005 mg, 83% yield) as a colorless viscous oil.
Step 4:
(S)-3-(tert-Butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-y-
l)-2-oxobutyl acetate
[0269] To a solution of
(S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propa-
noic acid (4000 mg, 11857 .mu.mol) in 100 mL of THF at 0.degree. C.
was added TEA (1653 .mu.l, 11857 .mu.mol) and isobutyl
chloroformate (1551 .mu.l, 11857 .mu.mol). Reaction was stirred at
0.degree. C. for 2 hours then filtered through a small frit of
celite. The filtered solution was cooled to 0.degree. C. and
freshly prepared diazomethane (0.5 M in ether, 35570 .mu.l, 17785
.mu.mol) was added. The reaction solution was maintained at
0.degree. C. for 1 hour then poured into saturated sodium
bicarbonate 250 mL. The aqueous layer was extracted with ethyl
acetate (3.times.100 mL). The combined organic layers were washed
with water and then brine and dried over Na.sub.2SO.sub.4.
Concentration under reduced pressure provided the diazo ketone as a
yellow oil that was carried on without further purification. The
diazo ketone was taken up in 100 mL of THF, cooled to 0.degree. C.
and treated with HBr (33 wt % in AcOH) (2147 .mu.l , 11857
.mu.mol). After stirring for 30 minutes potassium carbonate (2458
mg, 17785 .mu.mol) and sodium acetate (9726 mg, 118565 .mu.mol)
were added and the THF was removed in vacuo. 25 mL of DMF was added
and the reaction slurry was stirred at rt for 10 minutes, then
diluted with ethyl acetate (50 mL) and poured into water (100 mL).
The aqueous layer was extracted with ethyl acetate (2.times.100 mL)
and the combined organic layers were washed with water and then
brine and dried over Na.sub.2SO.sub.4. Concentration under reduced
pressure and purification of the crude by silica gel chromatography
(Analogix, 120 g) 0-25% ethyl acetate in hexanes provided
(S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-ox-
obutyl acetate (3560 mg, 76% yield) as a slightly yellow oil.
Step 5:
(2S,3S)-3-(tert-Butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-
-5-yl)-2-hydroxybutyl acetate
[0270] A solution of
(S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-ox-
obutyl acetate (3270 mg, 8311 .mu.mol) in 100 mL of ethanol was
cooled to -78.degree. C. and added to a solution of lithium
aluminum tri-tert-butoxyhydride (16623 .mu.l, 16623 .mu.mol) in 45
mL of ethanol at -78 C dropwise via a cannula over 10 minutes.
After stirring at -78 .degree. C. for 2 hours the reaction was
quenched with 25 mL of 1 N HCl and diluted with ethyl acetate (500
mL). The mixture was poured into 200 mL of water, the layers were
separated and the aqueous layer was extracted with ethyl acetate
(3.times.100 mL). The combined organics were washed with water,
brine, and dried over sodium sulfate and concentrated to provide
(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)--
2-hydroxybutyl acetate (3220 mg, 98% yield) as a white solid.
Step 6:
(4S,5S)-tert-butyl4-((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-
-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate
[0271] To a solution of
(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)--
2-hydroxybutyl acetate (1350 mg, 3414 .mu.mol) in 5 mL of DMF was
added 2-methoxyprop-1-ene (1961 .mu.l, 20483 .mu.mol) and
((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic
acid (397 mg, 1707 .mu.mol). After stirring for 20 hours the
reaction was poured into ice-cold aqueous saturated sodium
bicarbonate (150 mL) and extracted with ethyl acetate (3.times.50
mL). The combined organic layers were washed with water, brine, and
dried over sodium sulfate. The orange oil was taken up in 30 mL of
methanol, cooled to 0.degree. C. and treated with potassium
carbonate (1415 mg, 10242 .mu.mol). The reaction was allowed to
warm to rt over the course of 1 hour and stirred for a total of 2
hours. The reaction was diluted with ethyl acetate (25 mL) and
poured in saturated ammonium chloride 50 mL. The aqueous layer was
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were washed with water, brine dried over Na.sub.2SO.sub.4,
filtered, concentratd under reduced pressure and purification of
the resulting crude material by silica gel chromatography provided
(4S,5S)-tert-butyl4-((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-5-(hyd-
roxymethyl)-2,2-dimethyloxazolidine-3-carboxylate as an orange
foam.
Example 6 (9)
##STR00022##
[0272]
(4S)-2,2-Spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]py-
ridin-4-amine
Step 1: 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide
[0273] 5-(Methoxymethoxy)-2-neopentylpyridine (11.0 g, 52.6 mmol)
was dissolved in CH.sub.2Cl.sub.2 (200 mL) to which mCPBA (18.1 g,
105 mmol) was added, and the mixture was stirred under N.sub.2 for
about 4 h. The mixture was quenched with 1M NaOH (200 mL) and
stirring was continued vigorously for 10 min. The mixture was
extracted with CH.sub.2Cl.sub.2 (2.times.300 ML), the combined
organic layers were washed with saturated NaCl, dried
(Na.sub.2SO.sub.4), and evaporated to give
5-(methoxymethoxy)-2-neopentylpyridine-N-oxide (11.8 g, 99.7%
yield) as a brown oil which was used without purification in the
next step.
Step 2: 3-(methoxymethoxy)-6-neopentylpicolinonitrile
[0274] 5-(Methoxymetboxy)-2-neopentylpyridine-N-oxide (11.5 g, 51
mmol) was dissolved in CH.sub.2Cl.sub.2 (50 mL) to which benzoyl
chloride (12 ml, 102 mmol) and (trimethylsilyl)formonitrile (14 ml,
102 mmol) were added. The mixture was stirred under N.sub.24 h,
quenched with saturated NaHCO.sub.3 (150 mL), and extracted with
CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic layers were
washed with saturated NaHCO.sub.3 (2.times.50 mL), dried
(MgSO.sub.4), and evaporated to give the crude product as a brown
oil, which was purified by ISCO (330 g SiO.sub.2, 0-40%
EtOAc/Hexane) to give 3-(methoxymethoxy)-6-neopentylpicolinonitrile
(8.8 g, 74% yield) as a clear oil.
Step 3: 1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone
[0275] 3-(Methoxymethoxy)-6-neopentylpicolinonitrile (8.3 g, 35
mmol) was dissolved in THF (125 mL). The solution was cooled to
0.degree. C. and methylmagnesium chloride (24 ml, 71 mmol) (3.0 M
in Et.sub.2O) was added. The reaction mixture stirred for 2 h at rt
under N.sub.2 then quenched with saturated NH.sub.4Cl (50 mL) and
extracted with EtOAc (3.times.50 mL). The organic layer was dried
over MgSO.sub.4 and evaporated to give the crude product as a
yellow oil. Purification of the crude residue by ISCO (40 g
SiO.sub.2, 0-40% EtOAc/Hexane) gave
1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone (3.8 g, 43%
yield) as a clear, light orange oil.
Step 4: 1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone
[0276] A solution of
1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone (3.75 g, 15
mmol) in (2:1:1) 5 M HCl : i-PrOH: THF (100 mL) was stirred 16 h at
rt. The mixture was concentrated to remove the THF and i-PrOH. The
resulting solution consisting of the product in aqueous HCl was
quenched by slow addition to a solution of saturated aqueous
NaHCO.sub.3 (500 mL) containing excess solid NaHCO.sub.3 (28 g).
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3.times.100
mL), the organic layers combined and washed with saturated aqueous
NaCl (100 mL), dried (MgSO.sub.4), and concentrated to give the
crude product as a brown oil. The product was purified by ISCO
(0-10% EtOAc/Hexanes) to give
1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone (1.98 g, 64% yield)
as a clear, colorless oil.
Step 5:
2,2-spirocyclobutan-6-neopentyl-2,3-dihydropyrano[3,2-b]pyridin-4--
one
[0277] A mixture of 1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone
(1.90 g, 9167 .mu.mol), pyrrolidine (2296 .mu.l , 27501 .mu.mol),
and cyclobutanone (2570 mg, 36667 .mu.mol) in CH.sub.3CN (20 mL)
was heated in a 65.degree. C. oil bath for 3 h. The mixture was
cooled to rt, then diluted with EtOAc (25 mL), washed with
H.sub.2O, saturated aqueous NH.sub.4Cl, saturated aqueous NaCl,
dried (MgSO.sub.4), and concentrated. Purification of the resulting
crude material by ISCO (40 g SiO.sub.2, 10-20% EtOAc/Hexanes) gave
2,2-spirocyclobutan-6-neopentyl-2,3-dihydropyrano[3,2-b]pyridin-4-one
(710 mg, 29.9% yield) as a yellow solid.
Step 6:
(4R)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]p-
yridin-4-ol
[0278] To a vial containing
2,2-spirocyclobutan-6-neopentyl-2,3-dihydropyrano[3,2-b]pyridin-4-one
(710 mg, 2738 .mu.mol) was added sodium formate (1862 mg, 27377
.mu.mol) and tetrabutylammonium bromide (26.5 mg, 82.1 .mu.mol).
Toluene (5 mL) and H.sub.2O (2.5 mL) were added and the solution
purged 3.times.with N.sub.2, then with an Ar balloon for 15 min.
[(1R,2R)-2-Amino-1,2-diphenyl-N-(p-tolylsulfonyl)ethylamido]chloro(.eta..-
sup.6-p-cymene)ruthenium (II) (53.4 mg, 82.1 .mu.mol) was added and
the biphasic reaction was stirred at rt under Ar for 24 h. H.sub.2O
(10 mL) was added and the reaction was extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The combined organic layers were
dried (Na.sub.2SO.sub.4), and concentrated to give a brown oil,
which was purified by ISCO (40 g SiO.sub.2, 5-40% EtOAc/Hexane)
gives
(4R)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin--
4-ol (460 mg, 64.3% yield) as a clear oil.
Step 7:
(4S)-4-azido-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano-
[3,2-b ]pyridine
[0279] To a solution of
(4R)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin--
4-ol (460 mg, 1760 .mu.mol) in toluene (4 mL) is added
diphenylphosphoryl azide (531 .mu.l, 2464 .mu.mol) then
1,8-diazabicyclo(5.4.0)-7-undecene (368 .mu.l, 2464 .mu.mol). The
reaction mixture was stirred under N.sub.2 at rt 23 h. The clear,
light yellow solution first turned into a brown cloudy/opaque
solution after 30 min. To speed up the reaction rate, the mixture
was heated to 40.degree. C. and stirred an additional 5 h. Water
(20 mL) was added and the reaction mixture was extracted with EtOAc
(3.times.20 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), and concentrated to give the crude product as a
brown oil, which was purified by ISCO (40 g SiO.sub.2, 0-20%
EtOAc/Hexane) gives
(4S)-4-azido-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[-
3,2-b]pyridine (250 mg, 49.6% yield) as a white solid.
Step 8:
(4S)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]p-
yridin-4-amine
[0280] A solution of
(4S)-4-azido-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]-
pyridine (250 mg, 873 .mu.mol) in methanol (10 mL) was purged with
N.sub.2 (3.times.), then palladium (260 mg, 244 .mu.mol) (10 wt %
on carbon) was added. The reaction was purged with H.sub.2
(3.times.), then stirred at rt under H.sub.2 1.5 h. The suspension
was filtered through a pad of Celite, MeOH wash (4.times.5 mL), and
the solution concentrated to give the crude product (245 mg) as a
white oily solid, which was purified by ISCO (12 g SiO.sub.2, 0-10%
MeOH/CH.sub.2Cl.sub.2) to give the title compound as a white
solid.
Example 7
##STR00023##
[0281]
(4S)-6-(1,1-Difluoroethoxy)-2,2-spirocyclobutan-3,4-dihydro-2H-pyra-
no[2,3-b]pyridin-4-amine.
Step 1:
(4S)-tert-Butyl-6-acetyl-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano-
[2,3-b]pyridin-4-yl(allyl)carbamate.
[0282] To a solution of
(4S)-tert-butyl6-bromo-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]py-
ridin-4-yl(allyl)carbamate (8.1 g, 20 mmol) in Et.sub.2O (100 mL)
at -78.degree. C. was added tert-butyllithium (23 ml, 40 mmol) over
3 minutes. The reaction was allowed to stir 10 min. at -78.degree.
C., then acetaldehyde (4.5 ml, 79 mmol) was added, the reaction was
then warmed to rt over 30 min, and quenched with NH.sub.4Cl (200
mL). The reaction was extracted with EtOAc (3.times.100 mL), the
combined organic layers were washed with saturated NaCl (100 mL),
dried (Na.sub.2SO.sub.4), and concentrated to give crude product as
a dark yellow/orange oil. The crude was carried on into the next
step without purification. To a solution of the crude product from
above in CH.sub.2Cl.sub.2 (50 mL) at 0.degree. C., was added sodium
bicarbonate (6.64 g, 79.0 mmol) and Dess-Martin periodinane (10.5
g, 24.7 mmol) simultaneously. The ice bath was removed and the
reaction was stirred for 2 h at rt, then quenched with saturated
Na.sub.2SO.sub.3 (300 mL), extracted with CH.sub.2Cl.sub.2
(3.times.200 mL), and concentrated. The crude material was purified
by ISCO (10-50% EtOAc/Hexane) to give the title compound (4.10 g,
55.7% yield over 2 steps) as a clear, light yellow oil.
Step 2:
(4S)-1-(4-amino-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]py-
ridin-6-yl)ethanone
[0283] To a 150 mL rbf with
(4S)-tert-butyl6-acetyl-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]p-
yridin-4-yl(allyl)carbamate (2.05 g, 5504 .mu.mol) and
CH.sub.2Cl.sub.2 (50 mL) was added 2,2,2-trifluoroacetic acid (5089
.mu.l, 66048 .mu.mol). The reaction was allowed to stir at RT for 5
h, then diluted with CH.sub.2Cl.sub.2 (50 mL). The mixture was
washed with saturated NaHCO.sub.3 (2.times.100 mL) and the organic
layer degassed with Argon for 10 minutes. The degassed solution was
treated with 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (2.21 g,
14154 .mu.mol) and tetrakistriphenylphosphine palladium(0) (254 mg,
220 .mu.mol) and stirred at rt for 24 hours. The reaction mixture
was washed with NaOH (1N, 2.times.50 mL), and HCl (1N, 2.times.50
mL). The acidic aqueous layer was then basified to pH 14 with NaOH
(5N, 25 mL) and extracted with DCM (3.times.50 mL). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated to
give
(4S)-1-(4-amino-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-
-yl)ethanone (810 mg, 63.4%) as a light yellow oil.
Step 3:
(4S)-6-(1,1-difluoroethoxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyr-
ano[2,3-b]pyridin-4-amine
[0284] To a 20 mL polyethylene vial was added
(4S)-1-(4-amino-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-
-yl)ethanone (410 mg, 1765 .mu.mol) and HF/pyridine (1 mL). Xenon
difluoride (359 mg, 2118 .mu.mol) was added to the mixture followed
by CH.sub.2Cl.sub.2 (1 mL). The reaction was stirred at rt 24 h,
then quenched by slowly adding it to saturated NaHCO.sub.3 (100 mL)
with solid NaHCO.sub.3 (5 g). The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were
collected, dried (Na.sub.2SO.sub.4) and concentrated to give the
crude product as a brown oil. The crude was purified by ISCO
(2.times.12 g SiO.sub.2 stacker, 0-8% MeOH/CH.sub.2Cl.sub.2) to
give
(4S)-6-(1,1-difluoroethoxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-
-b]pyridin-4-amine as an orange oil.
Example 8
##STR00024##
[0285]
(1R,2S,4'S)-2-Hydroxy-3',4'dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
-b]pyridin-4'amine and
(1S,2R,4'S)-2-hydroxy-3',4'dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyr-
idin-4'-amine
Step 1: (cis)-1-Allyl-2-(benzyloxy)cyclobutanol and
(trans)-1-allyl-2-(benzaloxy)cyclobutanol
[0286] To a RBF under argon was added 2-(benzyloxy)cyclobutanone
(8.0 g, 45 mmol) and THF (100 mL). The reaction was cooled to
0.degree. C. and allylmagnesium bromide (113 ml, 113 mmol) (1.0 M
in Et.sub.2O) was added over 20 min. The clear colorless solution
turned into a tan solution with a white suspension. The ice bath
was removed and the reaction warmed to rt and stirred 7 h. The
reaction was quenched by slow addition to saturated aqueous
NH.sub.4Cl (500 mL). The reaction was diluted with EtOAc (300 mL)
and extracted. The aqueous layer was extracted with EtOAc
(2.times.250 mL), the combined organic layers washed with saturated
NaCl (250 mL), dried (Na.sub.2SO.sub.4), and concentrated to give a
clear, light yellow oil, which was purified by ISCO (330 g
SiO.sub.2, 10-40% EtOAc/Hexane) gives the less polar isomer
(cis)-1-allyl-2-(benzyloxy)cyclobutanol (4.0 g, 40% yield) followed
by the more polar isomer (trans)-1-allyl-2-(benzyloxy)cyclobutanol
(2.4 g, 24% yield) as a clear, colorless oils.
Step 2:
((1,2-cis)-1-Allyl-2-(benzaloxy)cyclobutoxy)(tert-butyl)dimethylsi-
lane
[0287] (Cis)-1-Allyl-2-(benzyloxy)cyclobutanol (4.00 g, 18.3 mmol)
was dissolved in CH.sub.2Cl.sub.2 (100 mL) to which
tert-butyldimethylsilyl trifluoromethanesulfonate (5.05 ml, 22.0
mmol) and N-ethyl-N-isopropylpropan-2-amine (3.99 ml, 22.9 mmol)
were added. The reaction mixture was stirred at rt for 5 h. The
reaction was quenched with 10% NaCO.sub.3 (300 mL), and the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The
combined organic layers were washed with saturated NaCl (50 mL),
dried (Na.sub.2SO.sub.4), and concentrated to give a yellow oil,
which was purified by ISCO (40 g SiO.sub.2, 100% Hexane to give
((cis)-1-allyl-2-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane
(5.38 g, 88.3% yield) as a clear, colorless oil.
Step 3: 2-((1,2-cis)-2-(Benzaloxy)-1-(tert-butyldimethylsilyloxy)
cyclobutyl)acetaldehyde
[0288]
((cis)-1-Allyl-2-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane
(5.37 g, 16 mmol) was dissolved in t-butanol (30 mL, 319 mmol) and
H.sub.2O (30 mL) followed by the addition of 4-methylmorpholine
n-oxide (3.4 g, 29 mmol) in one portion. After the reactants
dissolved, osmium tetroxide (5.1 mL, 0.40 mmol) was added and the
reaction mixture was stirred at RT for 17 h. The reaction mixture
was worked up by the addition of 6 g of sodium sulfite and allowed
to stir for 1 h. The reaction mixture was extracted with ether and
the organic phase was concentrated and used directly in the next
step. The crude was dissolved in 1:1 t-BuOH/H.sub.2O (60 mL) and
sodium periodate (6.2 g, 29 mmol) was added. The mixture was
stirred for 3 h. Then H.sub.2O (100 mL) was added and the mixture
was extracted with Et.sub.2O (3.times.100 mL). The combined organic
layers were dried (MgSO.sub.4) and concentrated. The crude was
purified by ISCO (120 g SiO.sub.2, 5-20% EtOAc/Hexane to give
2-((cis)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldeh-
yde (4.0 g, 74% yield) as a clear, colorless oil.
Step 4:
2-((1,2-cis)-2-(Benzaloxy)-1-(tert-butyldimethylsilyloxy)cyclobuty-
l)-1-(2-fluoro-5-neopentylpyridin-3-yl)ethanol
[0289] To a flame-dried 250 mL rbf with
2,2,6,6-tetramethylpiperidine (3.41 ml, 20.1 mmol) was added THF
(40 mL) and the solution is cooled to -78.degree. C. n-Butyllithium
(10.8 ml, 1.60 M, 17.2 mmol) was added dropwise and the reaction
was warmed to 0.degree. C. and stirred 5 min. The reaction was
recooled to -78.degree. C. and 2-fluoro-5-neopentylpyridine (2.40
g, 14.3 mmol) in THF (10 mL) was added and the reaction stirred 45
min at -78.degree. C. Then
2-((cis)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldeh-
yde (4.00 g, 12.0 mmol) in THF (10 mL) was added dropwise. The
reaction mixture was stirred 15 min at -78.degree. C., then
quenched by addition of saturated NH.sub.4Cl (50 mL), warmed to rt,
diluted with H.sub.2O (50 mL) and extracted with Et.sub.2O
(3.times.100 mL). The combined organic layers were washed with
saturated NaCl (100 mL), dried (Na.sub.2SO.sub.4), and concentrated
to give a crude product, which was purified by ISCO (120 g
SiO.sub.2, 0-20% EtOAc/Hexane) to give the title compound (5.18 g,
86.3%) as a 1:1 mixture of diastereomers, as a clear, light yellow
oil.
Step 5:
(1,2-cis)-2-(Benzyloxy)-1-(2-(2-fluoro-5-neopentylpyridin-3-yl)-2--
hydroxyethyl)cyclobutanol
[0290] To a flame-dried 100 mL rbf with
2-((1,2-cis)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2-
-fluoro-5-neopentylpyridin-3-yl)ethanol (5.18 g, 10 mmol) was added
THF (10 mL) followed by TBAF (12 ml, 1.0 M in THF, 12 mmol). The
reaction was stirred at rt for 30 min, then diluted with H.sub.2O
(100 mL) and extracted with Et.sub.2O (3.times.50 mL). The combined
organic layers were washed with saturated NaCl (100 mL), dried
(Na.sub.2SO.sub.4) and concentrated to give a crude materiall,
which was purified by ISCO (120 g SiO.sub.2, 0-20% EtOAc/Hexane) to
give
(1,2-cis)-2-(benzyloxy)-1-(2-(2-fluoro-5-neopentylpyridin-3-yl)-2-hydroxy-
ethyl)cyclobutanol (3.25 g, 81%) as a 1:1 mixture of diastereomers,
a clear, light yellow oil.
Step 6:
(1,2-cis)-2-Benzyloxy-6'neopentyl-3',4'dihydrospiro[cyclobutane-1,-
2'-pyrano[2,3-b]pyridin-4'-one
[0291] To a flame-dried 100 mL rbf with
(1,2-cis)-2-(benzyloxy)-1-(2-(2-fluoro-5-neopentylpyridin-3-yl)-2-hydroxy-
ethyl)cyclobutanol (3.06 g, 7.9 mmol) was added THF (500 mL)
followed by NaH (1.6 g, 39 mmol, 60% in mineral oil). The reaction
was heated in a 60.degree. C. oil bath under N.sub.2 for 4 h, then
cooled to rt and quenched with saturated NH.sub.4Cl (200 mL). The
aqueous layer was extracted with EtOAc (3.times.100 mL), and the
combined organic layers dried (MgSO.sub.4) and concentrated to give
the crude alcohol, which was used in the next step without
purification. The crude material was dissolved in CH.sub.2Cl.sub.2
(100 mL) and Dess-Martin periodinane (3.3 g, 7.9 mmol) and sodium
bicarbonate (0.66 g, 7.9 mmol) were added at the same time. The
reaction was stirred for 2 h at rt. The reaction was quenched with
saturated aqueous Na.sub.2SO.sub.3 (100 mL), extracted, then
extracted with additional CH.sub.2Cl.sub.2 (2.times.100 mL). The
combined organic layers were washed with saturated NaCl (100 mL),
dried (Na.sub.2SO.sub.4), and concentrated to give the crude
product as a yellow oil. Purification of the oil by ISCO (120 g
SiO.sub.2, 0-80% EtOAc/Hexane) gave the title compound (2.67 g,
93%) as a clear, light yellow oil.
Step 7:
(1R,2S,4'R)-2-Benzyloxy-3',4'dihydrospiro[cyclobutane-1,2'-pyrano[-
2,3-b-]pyridin-4'-ol
[0292] To a stirred solution of (s)-2-methyl-cbs-oxazaborolidine
(0.70 ml, 0.70 mmol) in THF (10 mL) at 0.degree. C. was added
borane-methyl sulfide complex (1.2 ml, 12 mmol) followed by a
solution of
(1,2-cis)-2-benzyloxy-6'neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-pyra-
no[2,3-b]pyridin-4'-one (2.57 g, 7.0 mmol) in THF (20 mL) dropwise
via syringe pump over about 2.8 h. The reaction was stirred an
additional 30 min, then was quenched by dropwise addition (1
drop/10 sec) of 5 M HCl (25 mL) at 0.degree. C. After 15 mL HCl was
added, bubbling had ceased and the addition rate was increased as
the ice bath was removed. The reaction was stirred an additional 2
h at rt. The reaction was recooled to 0.degree. C. and neutralized
with 5 M NaOH (27 mL). The mixture was then extracted with EtOAc
(2.times.150 mL), washed with saturated aqueous NaCl (200 mL),
dried (MgSO.sub.4), and concentrated to give a yellow oil.
Purification of the oil by ISCO (120 g SiO.sub.2, 20% EtOAc/Hexane)
gave a mixture of
(1R,2S,4'R)-2-benzyloxy-6'-neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-p-
yrano[2,3-b]pyridin-4'-ol (1.3 g, 50%) and (1S,2R,
4'R)-2-benzyloxy-6'-neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-pyrano[2-
,3-b]pyridin-4'-ol (1.3 g, 50%) as a white foam.
Step 9:
(1R2S,4'S)-2-Benzyloxy-6'-neopentyl-3'4'dihydrospiro[cyclobutane-1-
,2'-pyrano[2,3-b]pyridin-4'-azide and
(1S,2R,4'S)-2-benzyloxy-6'neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-py-
rano[2,3-b]pyridin-4'-azide
[0293] To a solution of (1,2-cis,
4'R)-2-benzyloxy-6'-neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-pyrano[2-
,3-b]pyridin-4'-ol (2.6 g, 7.1 mmol) (1:1 mixture of
1,2-spirocyclobutyl diastereomers) in toluene (14 mL) was added
diphenylphosphoryl azide (2.1 ml, 9.9 mmol) then
1,8-diazabicyclo(5.4.0)-7-undecene (1.5 ml, 9.9 mmol). The reaction
was stirred under N.sub.2 at rt for 18 h. The clear, light yellow
solution turned into a yellow cloudy/opaque solution after 10 min.
Water (100 mL) was added and the reaction mixture extracted with
EtOAc (3.times.200 mL). The combined organic layers were washed
with saturated NaCl (150 mL), dried (MgSO.sub.4), and concentrated
to give the crude product as a brown oil.
[0294] To a solution of the brown oil from above in 10:1
THF/H.sub.2O (40 mL) at 0.degree. C. is added NaOH (2.85 ml, 14.3
mmol). After 5 min, trimethylphosphine (2.52 ml, 28.5 mmol) was
added dropwise over 4 min. The ice bath was allowed to melt as the
reaction warmed to rt and stirred a total of 18 h. The mixture was
recooled to 0.degree. C. and 5 N HCl (50 mL) was added. The
resulting mixture was extracted with CH.sub.2Cl.sub.2 (3.times.100
mL), the combined organic layers were washed with 2.5 N HCl
(2.times.50 mL). The combined aqueous layers were cooled to
0.degree. C. and basified to pH 14 with 5 N NaOH (200 mL). The
aqueous layer was extracted with CH.sub.2Cl.sub.2 (3.times.100 mL)
the combined organic layers dried (Na.sub.2SO.sub.4), and
concentrated to give 2.9 g crude product as a viscous yellow oil.
Purification of the oil by ISCO (120 SiO.sub.2, 0-10%
MeOH/CH.sub.2Cl.sub.2 gradient elution) gave a 1:1 mixture of the
title compounds (1.870 g, 71.6% yield) as a yellow oil.
Step 10:
(1R,2S,4'S)-2-Hydroxy-6'-neopentyl-3',4'dihydrospiro[cyclobutane--
1,2'-pyrano[2,3-b]pyridin-4'-amine and
(1S,2R,4'S)-2-hydroxy-6'neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-pyra-
no[2,3-b]pyridin-4'-amine
[0295] To a solution of
(1,2-cis,4'S)-2-benzyloxy-6'neopentyl-3',4'dihydrospiro[cyclobutane-1,2'--
pyrano[2,3-b]pyridin-4'-azide (1.320 g, 3.6 mmol) in MeOH (50 mL)
under Ar is added Pd Black (76.7 mg, 720 .mu.mol). H.sub.2 gas was
bubbled though the suspension for 15 min. The reaction was then
stirred at rt under an atmosphere of H.sub.2 (balloon) for 48 h.
After 48 h, the H.sub.2 atmosphere was replaced with N.sub.2, and
palldium hydroxide (506 mg, 720 .mu.mol) was added, the reaction
was sparged with H.sub.2 and stirred for 24 h at rt. The H.sub.2
atmosphere was replaced with N.sub.2, and the suspension was
filtered through a plug of Celite, washed with MeOH (3.times.50
mL), and the combined filtrates were concentrated in vacuo to give
the crude product. Purification of the crude material by ISCO (120
g SiO.sub.2, 0-30% MeOH/CH.sub.2Cl.sub.2 gradient elution) gave a
mixture of
(1R,2S,4'S)-2-hydroxy-6'-neopentyl-3',4'dihydrospiro[cyclobutane-1,2'--
pyrano[2,3-b]pyridin-4'-amine (415 mg, 41.7% yield) and
(1S,2R,4'S)-2-hydroxy-6'neopentyl-3',4'dihydrospiro[cyclobutane-1,2'-pyra-
no[2,3-b]pyridin-4'-amine as a yellow solid.
[0296] The following intermeciate materials were made using a
procedure similar to that described in Examples 6, but with
different starting materials.
##STR00025## ##STR00026##
Example 9
##STR00027##
[0297]
(S)-3-(4-Amino-8-fluoro-2,2-spirocyclobutyl-6-yl)-2,2-dimethylpropa-
nenitrile
Step 1: 1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethanone
[0298] 4-Bromo-2-fluorophenyl acetate (126 g, 540 mmol) in
1,2-dichlorobenzene (53 mL) was added dropwise to aluminum(III)
chloride (72 g, 540 mmol) in 1,2-dichlorobenzene (64 mL) with
vigorous stirring to give a red solution. The solution was heated
to 120.degree. C. for 60 hours, cooled, diluted with DCM, and added
to 1N HCl at 0.degree. C. The layers were separated and the aqueous
layer was extracted with DCM. The combined organic layers were
washed with 1N HCl, water, brine, and dried over sodium sulfate and
concentrated. The crude material was taken up in hexanes and added
to aqueous 1N NaOH at 0.degree. C. The solid was collected and
washed with hexanes. The aqueous filtrate and solid were acidified
with concentrated HCl and extracted with ethyl acetate. The
combined organic layers were washed with water, brine, dried over
sodium sulfate, and concentrated. The crude solid was
recrystallized from MeOH to afford the title compound (46 g, 37%
yield).
Step 2: 6-Bromo-8-fluoro-2,2-spirocyclobutyl-4-one
[0299] 1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethanone (15.00 g, 64
mmol), pyrrolidine (8 ml, 97 mmol), DIPEA (11 ml, 64 mmol), and
cyclobutanone (9 ml, 129 mmol) were heated at 65.degree. C. for 12
hours. After cooling, the reaction was diluted with EtOAc and
washed with 1N HCl. The aqueous layer was extracted with EtOAc. The
organic layers were combined, washed with water, brine, dried over
sodium sulfate and concentrated. The residue was chromatographed on
a silica gel column (10:1 Hexanes/Ether) to afford the title
compound (9.73 g, 53% yield) as an orange solid. MS m/z: 285.0
(100%, M).
Step 3: (R)-6-Bromo-8-fluoro-2,2-spirocyclobutyl-4-ol
[0300] (s)-2-Methyl-cbs-oxazaborolidine, 1M in toluene (3.41 ml,
3.41 mmol) was added to a solution of borane-dimethyl sulfide (4.86
ml, 51.2 mmol) in 74 mL of toluene at 0.degree. C. After stirring
20 minutes, 6-bromo-8-fluoro-2,2-spirocyclobutyl-4-one (9.73 g,
34.1 mmol) was added via syringe pump in 106 mL of toluene over 1.5
hour at -5.degree. C. After stirring an additional 30 minutes at
-5.degree. C. the reaction was quenched by the addition of methanol
and then 1N HCl. The mixture was extracted with ethyl acetate and
the combined organic layers were washed 2.times. with 50% saturated
ammonium chloride, brine, and dried over sodium sulfate.
Concentration of the filterd organic layer afforded the title
compound as yellow oil.
Step 4: (S)-4-Azido-6-bromo-8-fluoro-2,2-spirocyclobutyl
[0301] Diphenyl azidophosphate (4.90 ml, 22.7 mmol) was added to a
solution of (R)-6-bromo-8-fluoro-2,2-spirocyclobutyl-4-ol (4.35 g,
15.2 mmol) and DBU (3.43 ml, 22.7 mmol) in toluene (28 mL). The
reaction was allowed to stir 48 hours and was filtered through a
pad of silica gel and washed with EtOAc. Concentration of the EtOAc
afforded the title compound.
Step 5: (S)-6-Bromo-8-fluoro-2,2-spirocyclobutyl-4-amine
[0302] Raney nickel (2800), slurry, in water (0.4 g, 6 mmol) was
added to (S)-4-azido-6-bromo-8-fluoro-2,2-spirocyclobutyl. (4.73 g,
15 mmol) dissolved in i-PrOH (150 mL). Hydrazine, monohydrate (5
ml, 76 mmol) was added and the reaction mixture was stirred 30
minutes before being filtered through a pad of Celite washing with
ethanol. The EtOH solvent was concentrated, and the resulting crude
material was purified by silica gel chromatography (20:1 DCM/MeOH
(2M NH.sub.3) to afford the title product. MS m/z: 269.0 (100%,
M-17).
Step 6:
(S)-tert-Butyl6-bromo-8-fluoro-2,2-spirocyclobutyl-4-ylcarbamate
[0303] (S)-6-Bromo-8-fluoro-2,2-spirocyclobutyl-4-amine (3.00 g, 10
mmol), TEA (2.2 ml, 16 mmol), and BOC-anhydride (3.0 g, 14 mmol)
were stirred in DCM (30 mL) for 12 hrs and concentrated. The crude
material was taken up in EtOAc and washed with saturated ammonium
chloride, water, brine, dried over sodium sulfate and concentrated.
The crude material was purified by recrystallization from methanol
and water to afford the title product as a white solid.
Step 7: (S)-tert-Butyl
allyl(6-bromo-8-fluoro-2,2-spirocyclobutyl-4-yl)carbamate
[0304]
(S)-tert-Butyl6-bromo-8-fluoro-2,2-spirocyclobutyl-4-ylcarbamate
(5.7 g, 15 mmol) was dissolved in DMF (70 mL) and cooled to
0.degree. C. NaH (0.71 g, 18 mmol) was added carefully to the
mixture and the solution was allowed to stir for 40 minutes. Allyl
bromide (1.4 ml, 16 mmol) was added and the reaction mixture was
stirred 45 minutes and then diluted with saturated aqueous ammonium
chloride. Water was added and the solution was extracted with
ether. The combined organic layers were washed with water, brine,
dried over magnesium sulfate, filtered and concentrated to afford
the title compound. MS m/z: 370.1 (100%, M-55).
Step 8: (S)-tert-Butyl
allyl(8-fluoro-6-(hydroxymethyl)-2,2-spirocyclobutyl-4-yl)carbamate
[0305] (S)-tert-Butyl
allyl(6-bromo-8-fluoro-2,2-spirocyclobutyl-4-yl)carbamate (6.30 g,
15 mmol) was dissolved in diethyl ether (75 mL) and cooled to
-78.degree. C. tert-butyllithium (1.7 M) (19 ml, 33 mmol) was added
dropwise to give a dark orange solution. After 20 minutes, DMF (13
ml, 163 mmol) was added and the solution was stirred for 45 minutes
before being quenched by the addition of saturated ammonium
chloride and water. The aqueous solution was extracted with EtOAc
and the combined organic layers were washed with water, brine,
dried over sodium sulfate and concentrated. The crude material was
dissolved in 80 mL of MeOH, cooled to 0.degree. C. and NaBH.sub.4
(0.84 g, 22 mmol) was added to the cooled mixture. After stirring
40 minutes the reaction mixture and was quenched by addition of
saturated ammonium chloride and water. The aqueous solution was
extracted with EtOAc and the combined organic layers were washed
with water, brine, dried over sodium sulfate and concentrated. The
crude residue was purified by column chromatography (4:1 Hex/EtOAc)
to give the title product.
Step 9: (S)-tert-Butyl
allyl(6-(2-cyano-2-methylpropyl)-8-fluoro-2,2-spirocyclobutyl-4-yl)
carbamate
[0306] Dibromotriphenylphosphorane (4.28 g, 10.1 mmol) was added to
a solution of (S)-tert-butyl
allyl(8-fluoro-6-(hydroxymethyl)-2,2-spirocyclobutyl-4-yl)carbamate
(3.48 g, 9.22 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.61 ml,
9.22 mmol) in DCM (80 mL) at 0.degree. C. After stirring 45 minutes
at 0.degree. C. and 30 minutes at ambient temperature, the reaction
was concentrated and taken up in THF (40 mL). In a seperate flask,
diisopropylamine (8.21 ml, 58.1 mmol) was added to THF (90 mL) and
the solution was cooled to -78.degree. C. n-Butyllithium (22.1 ml,
55.3 mmol) was added and the solution was stirred 20 minutes at
0.degree. C. Isobutyronitrile (4.96 ml, 55.3 mmol) was added and
the yellow solution was stirred 40 minutes at 0.degree. C. before
the intermediate benzyl bromide described above in THF (40 mL) was
added dropwise via addition funnel. The reaction was stirred at
0.degree. C. and after 1 hour was complete. The reaction was
quenched with saturated ammonium chloride and was extracted with
EtOAc and the combined organic layers were washed with water,
brine, dried over sodium sulfate and concentrated. The crude
material was purified by silica gel chromatography (1.5:1
Hex/EtOAc)to afford the title product. MS m/z: 373.3 (100%,
M-55).
Step 10:
(S)-3-(4-(Allylamino)-8-fluoro-2,2-spirocyclobutyl-6-yl)-2,2-dime-
thylpropanenitrile
[0307] (S)-tert-Butyl
allyl(6-(2-cyano-2-methylpropyl)-8-fluoro-2,2-spirocyclobutyl-4-yl)
carbamate (2.90 g, 6.8 mmol) and TFA (25 ml, 324 mmol) were stirred
in DCM (50 mL) for 3 hours and concentrated. The crude product was
taken up in DCM and 1 N NaOH and separated. The aqueous layer was
extracted with DCM and the combined organic layers were washed with
brine and dried over sodium sulfate. Concentration afforded the
title product which was used without further purification. MS m/z:
329.3 (100%, M+1).
Step 11:
(S)-3-(4-Amino-8-fluoro-2,2-spirocyclobutyl-6-yl)-2,2-dimethylpro-
panenitrile
[0308]
(S)-3-(4-(Allylamino)-8-fluoro-2,2-spirocyclobutyl-6-yl)-2,2-dimeth-
ylpropanenitrile was dissolved in degassed (N.sub.2) DCM (40 mL)
and 1,3-dimethylbarbituric acid (3.2 g, 20 mmol) was added. After
two minutes, Pd(PPh.sub.3).sub.4 (0.78 g, 0.68 mmol) was added and
the reaction was stirred at ambient temperature for 12 hours. The
reaction was diluted with DCM and 10% aqueous sodium carbonate and
the layers were separated. The aqueous layer was extracted with DCM
and the combined organic layers were washed with brine, dried over
sodium sulfate and concentrated. The crude product was purified by
silica gel chromatography (20:1 DCM/MeOH (2M NH.sub.3)) to afford
the title product. MS m/z: 289.2 (37%, M+1); 272.2 (100%,
M-16).
Example 10
##STR00028##
[0309]
(S)-8-Fluoro-2,2-tetrahydrospirofuranyl-6-neopentylchroman-4-amine
Step 1:
6-Bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-one
[0310] 1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethanone (0.200 g, 0.858
mmol), dihydrofuran-3(2H)-one (0.222 g, 2.57 mmol), and pyrrolidine
(0.142 ml, 1.72 mmol) were dissolved in MeCN (0.5 mL) and heated in
the microwave for 20 minutes fixed at 60.degree. C. After cooling,
the reaction was diluted with EtOAc and washed with 1N HCl. The
aqueous layer was extracted with EtOAc. The organic layers were
combined, washed with water, brine, dried over sodium sulfate, and
concentrated. The crude product was purified by silica gel
chromatography (1:4 EtOAc/hexanes) to afford the titled products.
MS m/z: 301.0 (100%, M).
Step 2:
(R)-6-Bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-ol
[0311] (s)-2-Methyl-cbs-oxazaborolidine (0.767 ml, 0.767 mmol) was
added to a solution of borane-methyl sulfide complex (1.09 ml, 11.5
mmol) in 16 mL of toluene at 0.degree. C. After stirring 20
minutes, 6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-one
(2.31 g, 7.67 mmol) was added via syringe pump in 23 mL of toluene
over 1.5 hour at -5.degree. C. After stirring an additional 30
minutes at -5.degree. C. the reaction was quenched by the addition
of MeOH and then 1N HCl. The mixture was extracted with ethyl
acetate and the combined organic layers were washed twice with 50%
saturated ammonium chloride, brine, and dried over sodium sulfate.
Concentration of the filtered organic layer afforded the titled
product as a yellow oil.
Step 3:
(S)-4-Azido-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman
[0312] Diphenylphosphoryl azide (1.93 ml, 8.96 mmol) was added to a
solution of
(R)-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-ol (1.81
g, 5.97 mmol) and DBU (1.35 ml, 8.96 mmol) in toluene (10 mL). The
reaction was allowed to stir 48 hours and was filtered through a
pad of silica gel with ethyl acetate. Concentration of the filtered
organic layer afforded the titled products which were used without
further purification.
Step 4.
(S)-6-Bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-yl-amine
[0313] Raney nickel (2800, as a slurry in water) (0.19 g, 3.3 mmol)
was added to
(S)-4-azido-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman.
(1.2 g, 3.7 mmol) dissolved in i-PrOH (50 mL). Hydrazine hydrate
(1.1 ml, 18 mmol) was added and the reaction was stirred 30 minutes
and then filtered through a pad of celite with ethanol,
concentrated, and purified by silica gel chromatography (20:1
DCM/MeOH-NH3) to afford the titled products. MS m/z: 302.1 (5%, M);
285.1 (100%, M-17).
Step 5:
(S)-8-Fluoro-2,2-tetrahydrospirofuranyl-6-neopentylchroman-4-amine
[0314] To zinc chloride, 0.5M solution in THF (31 ml, 15 mmol) was
added 2,2-dimethylpropylmagnesium chloride, 1.0 M solution in
diethyl ether (25 ml, 25 mmol) in a sealed tube and stirred 20
minutes. 1,1'-Bis(diphenylphosphino)ferrocene-palladium dichloride
(0.2 g, 0.3 mmol) was added to the mixture followed by
(S)-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-amine
(0.932 g, 3 mmol) in THF (8 mL). The tube was sealed and heated to
70.degree. C. for 12 h. The reaction was cooled and diluted with
DCM and an aq. solution of a 9:1 saturated ammonium
chloride/ammonium hydroxide and the layers were separated. The
aqueous layer was extracted with DCM, and the combined organic
layers were washed with a 9:1 saturated ammonium chloride/ammonium
hydroxide solution, water, brine, dried over sodium sulfate, and
concentrated. Purification of the crude concentrate by silica gel
chromatography (20:1 DCM/MeOH-NH3) afforded the title products.
Example 11
##STR00029##
[0315]
(S)-8,8-Difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydro-
quinolin-5-amine
Step 1:
(S)-tert-butyl7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroqu-
inolin-5-ylcarbamate
[0316]
(S)-7,7-Spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-am-
ine (3.47 g, 13.4 mmol), TEA (2.81 ml, 20.1 mmol), and
di-tert-butyl dicarbonate (2.93 g, 13.4 mmol) were stirred in DCM
(60 mL) for 12 hrs and concentrated. The crude material was taken
up in ethyl acetate and washed with saturated ammonium chloride,
water, brine, dried over sodium sulfate, and concentrated. The
crude material was purified by column chromotography (10:1 to 1:1
Hexanes/EtOAc) to afford the titled product.
Step 2: N-oxide of
(S)-tert-butyl7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin--
5-ylcarbamate
[0317] m-Chloroperbenzoic acid (0.662 g, 2.30 mmol) was added to a
solution of
(S)-tert-butyl7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin--
5-ylcarbamate (0.688 g, 1.92 mmol) in DCM (20 mL) and the solution
was stirred 12 hrs before being diluted with aqueous saturated
sodium bicarbonate and aqueous sodium thiosulfate. The mixture was
stirred vigorously for 1.5 hrs then separated. The aqueous layer
was extracted with DCM and the combined organic layers were washed
with aqueous sodium thiosulfate, 10% sodium carbonate, water,
brine, and dried over sodium sulfate. The organic layer was filterd
and concentrated to afford the title product.
Step 3:
(S)-tert-Butyl8-hydroxy-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-te-
trahydroquinolin-5-ylcarbamate
[0318] The N-oxide from above (0.719 g, 1.92 mmol, Step 2) was
dissolved in DCM (9 mL). Trifluoroacetic anhydride (1.33 ml, 9.60
mmol) was added and the reaction was refluxed for 2 hours and
concentrated. The crude product was dissolved in THF (4.5 mL) and
aqueous saturated sodium bicarbonate was added by pipette in
dropwise fashion until no further bubbling was observed. The
reaction was diluted with ethyl acetate and water and the layers
were separated. The aqueous layer was extracted with ethyl acetate
and the combined organic layers were washed with water, brine, and
dried over sodium sulfate, filtered and concentrated. The crude
product was purified by silica gel chromatography (25:1 DCM/MeOH)
to afford the titled product. MS m/z: 375.3(100%, M+1).
Step 4:
(S)-tert-Butyl7,7-spirocyclobutyl-3-neopentyl-8-oxo-5,6,7,8-tetrah-
ydroquinolin-5-ylcarbamate
[0319]
(S)-tert-Butyl8-hydroxy-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tet-
rahydroquinolin-5-ylcarbamate (0.285 g, 0.761 mmol) and Dess-Martin
Periodinane (0.968 g, 2.28 mmol) were stirred 12 hrs in DCM (7 mL).
The reaction was diluted with ether and aqueous sodium thiosulfate
and saturated aqueous sodium bicarbonate and stirred vigorously.
The layers were separated and the aqueous layers were extracted
with ether and the combined organic layers were washed with
saturated aqueous sodium bicarbonate and water and concentrated.
The residue was taken up in ethyl acetate and washed with brine,
dried over sodium sulfate, and concentrated. Purification by silica
gel chromatography (1:1 Hexanes/EtOAc) afforded the titled product.
MS m/z: 373.3 (100%, M+1).
Step 5:
(S)-tert-Butyl8,8-difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-
-tetrahydroquinolin-5-ylcarbamate
[0320]
(S)-tert-Butyl7,7-spirocyclobutyl-3-neopentyl-8-oxo-5,6,7,8-tetrahy-
droquinolin-5-ylcarbamate (0.183 g, 0.491 mmol) was dissolved in
DCM (1.5 mL) and cooled to -78.degree. C. DAST (0.130 ml, 0.983
mmol) was added and the reaction mixture was allowed to warm to RT
over 12 hrs and stirred for four additional days. The reaction was
diluted with DCM and aqueous 10% sodium carbonate and separated.
The aqueous layer was extracted with DCM and the combined organic
layers were washed with water, brine, and dried over sodium
sulfate. Concentration of the filtered organic solvent afforded the
titled product. MS m/z: 395.2 (100%, M+1).
Step 6:
(S)-8,8-Difluoro-7,7-spirocyclobutyl-3-neopentlyi-5,6,7,8-tetrahyd-
roquinolin-5-amine
[0321]
(S)-tert-Butyl8,8-difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8--
tetrahydroquinolin-5-ylcarbamate (0.194 g, 0.49 mmol) was stirred
in a 2:1 solution of DCM and TFA (4.5 mL) for 3 hours and
concentrated. The crude product was taken up in chloroform and 1N
aq. NaOH and the layers were separated. The aqueous layer was
extracted with chloroform and the combined organic layers were
washed with brine, dried over sodium sulfate, filtered and
concentrated. The crude product was purified by silica gel
chromatography (30:1 DCM/MeOH-NH.sub.3) to afford the titled
product. MS m/z: 295.2 (100%, M+1).
Example 12
##STR00030##
[0322]
(1S,3S,4'S)-3-Hydroxy-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,-
3-c]pyridin-4'-amine
Step 1: 3-(Methoxymethoxy)pyridine
[0323] Pyridin-3-ol (25 g, 260 mmol) was added to a stirring
mixture of NaH (11 g of a 60 wt % dispersion with mineral oil, 260
mmol) and DMF (350 mL) at 0.degree. C. After 30 min, the reaction
mixture was allowed to warm to RT, stirred for 90 min, and then
chloromethoxymethane (20 mL, 260 mmol) was added. After 18 h, the
reaction mixture was partitioned between ethyl acetate and
saturated aqueous NaHCO.sub.3. The layers were separated, the
organic material was washed with saturated aqueous NaHCO.sub.3,
brine, dried (Na.sub.2SO.sub.4), filtered, and the filtrate was
concentrated. The residue was dissolved with CH.sub.2Cl.sub.2, the
solution was filtered through a plug of silica gel (sequential
elution; 9:1.fwdarw.1:1 hexane-ethyl acetate), and the second
filtrate was concentrated to give 10 g (27%) of
3-(methoxymethoxy)pyridine as a clear yellow oil.
Step 2: 1-(3-(Methoxymethoxy)pyridin-4-yl)ethanol
[0324] A solution of 3-(methoxymethoxy)pyridine (9.8 g, 70 mmol)
and THF (40 mL) was added to a stirring mixture of
tert-butyllithium (91 mL of a 1.7 M solution with pentane, 160
mmol) and THF (100 mL) at -78.degree. C. After 1 h, acetaldehyde
(9.9 mL, 180 mmol) was added, and the reaction mixture was stirred
for 3 h and then warmed to RT. After 21 h, the reaction mixture was
partitioned between ethyl acetate and saturated aqueous
NaHCO.sub.3, the layers were separated, the organic material was
washed with saturated aqueous NaHCO.sub.3, brine, dried
(Na.sub.2SO.sub.4), filtered, and the filtrate was concentrated.
The residue was purified by flash chromatography on silica gel (1:1
hexane-ethyl acetate) to afford 4.6 g (36%) of
1-(3-(methoxymethoxy)pyridin-4-yl)ethanol as a colorless solid.
Step 3: 1-(3-(methoxymethoxy)pyridin-4-yl)ethanone
[0325] Dess-Martin periodinane (18 g, 43 mmol) was added to a
stirring mixture of of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol
(4.6 g, 25 mmol), NaHCO.sub.3 (6.3 g, 75 mmol), and CHCl.sub.3 (75
mL) at RT. After 24 h, 1.0 M aqueous Na.sub.2S.sub.2O.sub.3 was
added, the reaction mixture was stirred for 90 min, partitioned
between ethyl acetate and 1.0 M aqueous Na.sub.2S.sub.2O.sub.3, the
layers were separated, the organic material was washed with 1.0 M
aqueous Na.sub.2S.sub.2O.sub.3, water, brine, dried
(Na.sub.2SO.sub.4), filtered, and the filtrate was concentrated.
The residue was purified by flash chromatography on silica gel
(gradient elution; 2:1.fwdarw.1:1 hexane-ethyl acetate) to give 3.9
g (86%) of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanone as a clear
yellow-orange oil.
Step 4:
(1S,3S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane--
1,2'-pyrano[2,3-c]pyridin-4'-one, and
(1S,3R)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospirorcyclobutane-1,2'-py-
rano[2,3-c]pyridin-4'-one
[0326] 3-(tert-Butyldimethylsilyloxy)cyclobutanone (15 g, 77 mmol),
1-(3-Hydroxypyridin-4-yl)ethanone (10.5000 g, 77 mmol) and
pyrrolidine (19 ml, 230 mmol) were dissolved in 500 ml CH.sub.3CN
and stirred at 65.degree. C. for 2 h. TLC analysis revealed the
disappearance of the SM and the formation of a single new spot. The
mixture was evaporated (100 ml residue) and partitioned between
water and EtOAc. The phases were separated and the aqueous was
extracted 3.times. with EtOAc. The combined organic extracts were
dried over MgSO.sub.4 and evaporated and the mixture was purified
via glass col. chromatography. The title compounds (8.500 g, 35%
yield) were obtained as a yellow solid (1:1 mixture of stereo
isomers)
Step 5:
(1S,3S,4'R)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospirorcyclobut-
ane-12'-pyrano[2,3-c]pyridin-4'-ol;
(1S,3R,4'R)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospirorcyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-ol
[0327]
(1S,3S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1-
,2'-pyrano[2,3-c]pyridin-4'-one and
(1S,3R)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2'-py-
rano[2,3-c]pyridin-4'-one (1:1 mixture of stereo isomers) (8.5000
g, 26.61 mmol) were dissolved in 150 ml toluene and 50 ml water was
added. Ar gas was bubbled through the mixture for 15 min.
Tetrabutylammonium bromide (0.2573 g, 0.7982 mmol), sodium formate
(18.09 g, 266.1 mmol) and TPAP (0.5190 g, 0.7982 mmol) were added
and the mixture was stirred for 14 h under an Ar atmosphere. The
mixture was partitioned between EtOAc and water and the phases were
separated. The aqueous was extracted 3 times with EtOAc, dried over
MgSO.sub.4 and evaporated. Glass col. chrom (10-50% EtOAc in hex.)
provided the title compounds (6.630 g, 77.51% yield) as yellow oil.
(1:1 mixture of stereo isomers). MS m/z: 322.2 (M+1).
Step 6:
(1S,3S,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobut-
ane-1,2'-pyrano[2,3-c]pyridin-4'-azide;
(1S,3R,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-azide
[0328]
(1S,3S,4'R)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobuta-
ne-1,2'-pyrano[2,3-c]pyridin-4'-ol,
(1S,3R,4'R)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-ol (1:1 mixture of stereo isomers)
(6.6300 g, 20.62 mmol), diphenyl azidophosphate (6.667 ml, 30.93
mmol) and DBU (4.626 ml, 30.93 mmol) were dissolved in 40 ml
CH.sub.2Cl.sub.2 and stirred over the weekend. Monitoring revealed
that the starting materials were almost consumed and product
formed, but still a large portion of the phosphonate ester
remained. 40 ml of Water was added and the mixture was extracted 3
times with Et.sub.2O, dried over MgSO.sub.4 and evaporated. The
crude product was used w/o purification in the next step. MS m/z:
347.2 (M+1).
Step 7:
(1S,3S,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospirorcyclobut-
ane-1,2'-pyrano[2,3-c]pyridin-4'-amine;
(1S,3R4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2'-
-pyrano[2,3-c]pyridin-4'-amine
[0329] The crude
(1S,3S,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-azide and
(1S,3R,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-azide (1:1 mixture of stereo isomers)
from the previous reaction (6.9 g, 20 mmol) was dissolved in 200 ml
THF and lithium aluminum hydride, 2M in THF (30 ml, 60 mmol) was
added at 0.degree. C. The mixture was stirred for 60 min and
hydrolyzed with Na.sub.2SO.sub.4-10H.sub.2O until gas evolution had
ceased. The mixture was filtered and evaporated and purified.
(2-10% MeOH in CH.sub.2Cl.sub.2) glass col. chromatography provided
the title compounds) as a yellow oil as a mixture of diastereomers.
The diastereomers were separated by SFC.
(1S,3S,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-amine (1.200 g, 19% yield) and
(1S,3R,4'S)-3-tert-Butyldimethylsiloxy-3',4'-dihydrospiro[cyclobutane-1,2-
'-pyrano[2,3-c]pyridin-4'-amine were obtained. MS m/z: 321.2
(M+1).
[0330] The following intermeciate materials were made using a
procedure similar to that described in Examples 12, but with
different starting materials.
##STR00031##
Example 13
##STR00032##
[0331]
(4'S)-6'-(2-Fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1-
,2'-pyranol2,3-c]pyridin-4'amine
Step 1: 1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol
[0332] 5-(Methoxymethoxy)-2-methylpyridine (22.1500 g, 144.6 mmol)
was dissolved in 1500 ml THF and cooled to -78.degree. C.
tert-Butyllithium (97.82 ml, 166.3 mmol) was added and the mixture
was stirred for 15 min. Acetone, (42.52 ml, 578.4 mmol) was added
and stirring of the mixture was continued for 15 min. The reaction
was hydrolyzed with 300 ml H.sub.2O and extracted with 4 L EtOAc
(2.times.). The combined organic extracts were dried over
MgSO.sub.4 and evaporated. Glas col. chrom (20-100% EtOAc provided
the 2 products:
1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol (7.5000 g,
24.55% yield) and
2-(5-(methoxymethoxy)-2-methylpyridin-4-yl)propan-2-ol (15.00 g,
49.10% yield). MS m/z: 212.0 (M+1).
Step 2: 2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine
[0333] 1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol
(7.600 g, 36.0 mmol) was dissolved in 200 ml CH.sub.2Cl.sub.2 and
cooled to -78.degree. C. DAST (9.51 ml, 72.0 mmol) was added drop
wise to the solution and stirring was continued for 30 min The
mixture was allowed to warm up to 0.degree. C. and was hydrolyzed
with NaHCO.sub.3 (200 ml). Stirring was continued in the cold until
gas evolution had ceased and the phases were separated. The aqueous
was extracted 2.times. with EtOAc and the combined organic layers
were dried over MgSO.sub.4 and evaporated. Glass col.
Chromatography of the crude material provided
2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.80 g,
75.6% yield) as a pale yellow oil.
Step 3:
1(2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridin-4-yl)ethan-
ol.
[0334] 2,2,6,6-Tetramethylpiperidine (8.26 ml, 49.0 mmol) was
dissolved with 270 ml THF and 1-butyllithium (14.1 ml, 35.4 mmol)
was added at -78.degree. C. The mixture was stirred for 10 min in
an ice bath and cooled back to -78.degree. C. A solution of
2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.8000 g,
27.2 mmol) in 20 ml THF was added dropwise and the reaction was
stirred for 20 min. Acetylaldehyde (7.65 ml, 136 mmol) was added to
the dark red solution and the color disappeared. Stirring was
continued for 20 min and the mixture was hydrolyzed with 50 ml of
water. The mixture was warmed to RT and extracted 3.times. with
CH.sub.2Cl.sub.2 (300 ml each). The combined organic extracts were
dried over MgSO.sub.4 and evaporated and purified via glass col.
chrom. (30-80% EtOAc in hex.) to provide
1-(2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridin-4-yl)ethanol
a white solid. MS m/z: 258.2 (M+1).
Example 14
##STR00033##
[0335]
(4S)-6-(2,2-Difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,-
3-b]pyridin-4-amine
Step 1:
(4S)-tert-Butyl6-(2-oxopropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyran-
o[2,3-b]pyridin-4-ylcarbamate
[0336] Anhydrous, de-gassed THF (20 mL) was added to
2-(dicyclohexylphosphino)-2'-methylbiphenyl (1.2 g, 3.2 mmol) and
tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g,
1.4 mmol), and the resulting solution was warmed to 45.degree. C.
and sparged with N.sub.2. After 20 min, the reaction mixture was
allowed to cool to RT, then added to a stirring, degassed mixture
of
(S)-tert-butyl6-bromo-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin--
4-ylcarbamate (10 g, 27 mmol), finely ground potassium phosphate
tribasic (14 g, 68 mmol), and acetone (100 mL, 1400 mmol) at RT,
and the resulting mixture was sparged with N.sub.2. After 20 min,
the reaction mixture was heated at reflux for 24 h. The reaction
mixture was allowed to cool to RT, filtered through a 0.45 .mu.m
Teflon filter, and the filtrate was concentrated. The residue was
purified by flash chromatography on silica gel (gradient elution;
1:1 -2:1 ethyl acetate-hexane) to afford 3.7 g (39%) of
(S)-tert-butyl6-(2-oxopropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyra-
no[2,3-b]pyridin-4-ylcarbamate as a yellow solid.
Step 2:
(4S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2-
H-pyrano[2,3-b]pyridin-4-ylcarbamate
[0337] Diethylaminosulfurtrifluoride (13 mL, 110 mmol) was added to
a stirring solution of
(s)-tert-butyl6-(2-oxopropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]-
pyridin-4-ylcarbamate (3.7 g, 11 mmol), ethanol (0.12 mL, 2.2
mmol), and CH.sub.2Cl.sub.2 (55 mL) at RT. After 24 h, the reaction
mixture was added to a rapidly stirring solution of aqueous 10%
Na.sub.2CO.sub.3. After 1 h, ethyl acetate was added, the layers
were separated, the organic material was washed sequentially with
aqueous 10% Na.sub.2CO.sub.3 and brine, dried (Na.sub.2SO.sub.4),
filtered, and the filtrate was concentrated. The residue was
purified by flash chromatography on silica gel (49:1
CH.sub.2Cl.sub.2-methanol) to afford 1.8 g (46%) of
(S)-tert-butyl6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano-
[2,3-b]pyridin-4-ylcarbamate as a yellow solid.
Step 3:
(S)-6-(2,2-Difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,-
3-b]pyridin-4-amine
[0338] Hydrogen chloride (12 mL of a 4.0 M solution with
1,4-dioxane, 49 mmol) was added to a stirring solution of
(4S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyran-
o[2,3-b]pyridin-4-ylcarbamate (1.8 g, 4.9 mmol) and
CH.sub.2Cl.sub.2 (49 mL) at RT. After 24 h, the reaction mixture
was concentrated, the residue was partitioned between aqueous 10%
Na.sub.2CO.sub.3 and EtOAc, the layers were separated. The organic
layer was washed with aqueous 10% Na.sub.2CO.sub.3, brine, dried
(Na.sub.2SO.sub.4), filtered, and the filtrate was concentrated to
afford
(S)-6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyr-
idin-4-amine as a yellow oil.
Example 15
##STR00034##
[0339]
(S)-6-(2,2-Difluoropropyl)-2,2-(2',2'-difluorocyclobutyl)-3,4-dihyd-
ro-2H-pyrano[2,3-b]pyridin-4-amine
Step 1: 1-(6-Fluoropyridin-3-yl)propan-2-one
[0340] Anhydrous, de-gassed THF (20 mL) was added to
2-(dicyclohexylphosphino)-2'-methylbiphenyl (1.2 g, 3.2 mmol) and
tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g,
1.4 mmol), and the resulting solution was warmed to 45.degree. C.
and sparged with N.sub.2. After 20 min, the reaction mixture was
allowed to cool to RT, then added to a stirring, degassed mixture
of 5-bromo-2-fluoropyridine (4.8 g, 27 mmol), finely ground
potassium phosphate tribasic (14 g, 68 mmol), and acetone (100 mL,
1400 mmol) at RT, and the resulting mixture was sparged with
N.sub.2. After 20 min, the reaction mixture was heated at reflux
for 24 h, the reaction mixture was allowed to cool to room
temperature, filtered through a 0.45 .mu.m Teflon filter, and the
filtrate was concentrated. The residue was purified by flash
chromatography on silica gel (gradient elution; 4:1.fwdarw.2:1
hexane-ethyl acetate) to give 2.3 g (55%) of
1-(6-fluoropyridin-3-yl)propan-2-one as a brown oil.
Step 2: 5-(2,2-Difluoropropyl)-2-fluoropyridine
[0341] Diethylaminosulfurtrifluoride (9.8 mL, 75 mmol) was added to
a stirring solution of 1-(6-fluoropyridin-3-yl)propan-2-one (2.3 g,
15 mmol), ethanol (0.18 mL, 3.0 mmol), and CH.sub.2Cl.sub.2 (60 mL)
at RT. After 24 h, the reaction mixture was added to a rapidly
stirring solution of aqueous 10% Na.sub.2CO.sub.3. After 1 h, ethyl
acetate was added, the layers were separated, the organic layer was
washed sequentially with aqueous 10% Na.sub.2CO.sub.3 and brine,
dried (Na.sub.2SO.sub.4), filtered, and the filtrate was
concentrated. The residue was purified by flash chromatography on
silica gel (9:1 hexane-ethyl acetate) to afford 1.5 g (57%) of
5-(2,2-difluoropropyl)-2-fluoropyridine as a yellow-orange oil.
Step 3:
(4S)-2-(1,3-Bis(tert-butyldimethylsiloxy)cyclobutyl)-1-(5-(2,2-dif-
luoropropyl)-2-fluoropyridin-3-yl)-ethyl-((R)-tert-butylsulfinyl)amine
[0342] Butyllithium (4.1 mL of a 2.5 M solution with toluene, 10
mmol) was added to a stirring solution of
2,2,6,6-tetramethylpiperidine (2.0 mL, 12 mmol) and THF (43 mL) at
-78.degree. C. After 5 min, the reaction mixture was raised above
the cooling bath for 10 min, re-cooled to -78.degree. C., and then
a solution of 5-(2,2-difluoropropyl)-2-fluoropyridine (1.5 g, 8.6
mmol) and THF (8.6 mL) was added. After 30 min, a solution of
2-(1,3-bis(tert-butyldimethylsiloxy)cyclobutyl)
acetaldehyde(R)-tert-butylsulfinylimine (4.4 g, 9.4 mmol) and THF
(9.4 mL) was added. After 20 min, saturated aqueous NaHCO.sub.3 was
added, the reaction mixture was allowed to warm to RT, partitioned
between saturated aqueous NaHCO.sub.3 and ethyl acetate, the layers
were separated, the organic layer was washed with saturated aqueous
NaHCO.sub.3, brine, dried (NaSO.sub.4), filtered, and the filtrate
was concentrated. The residue was purified by flash chromatography
on silica gel (gradient elution; 4:1.fwdarw.3:1.fwdarw.2:1
hexane-ethyl acetate) to afford 2.9 g (53%) of
(4S)-2-(1,3-bis(tert-butyldimethylsiloxy)cyclobutyl)-1-(5-(2,2-difluoropr-
opyl)-2-fluoropyridin-3-yl)-ethyl-((R)-tert-butylsulfinyl) amine as
a yellow solid.
Step 4:
(S)-6-(2,2-difluoropropyl)-2,2-((R)-2'-hydroxy)cyclobutyl-3,4-dihy-
dro-2H-pyrano[2,3-b]pyridin-4-amine and
(S)-6-(2,2-difluoropropyl)-2,2-((S)-2'-hydroxy)cylobutyl-3,4-dihydro-2H-p-
yrano[2,3-b]pyridin-4-amine
[0343] Hydrogen fluoride (24 mL of a 70 wt % solution with
pyridine, 1300 mmol) was added to
(S)-2-(1,3-bis(tert-butyldimethylsiloxy)cyclobutyl)-1-(5-(2,2-difluoropro-
pyl)-2-fluoropyridin-3-yl)-ethyl-((R)-tert-butylsulfinyl)amine (1.7
g, 2.7 mmol) in Teflon.TM. reaction vessel, and the reaction
mixture was heated at 80.degree. C. After 48 h, the reaction
mixture was added to aqueous 10% Na.sub.2CO.sub.3, the mixture was
stirred vigorously for 2 h, ethyl acetate was added, the layers
were separated, the organic material was washed with aqueous 10%
Na.sub.2CO.sub.3, brine, dried (Na.sub.2SO.sub.4), filtered, and
the filtrate was concentrated to afford 0.64 g (84%) of a mixture
of
(S)-6-(2,2-difluoropropyl)-2,2-((R)-2'-hydroxy)cyclobutyl-3,4-dihydro-2H--
pyrano[2,3-b]pyridin-4-amine and
(S)-6-(2,2-difluoropropyl)-2,2-((S)-2'-hydroxy)cyclobutyl-3,4-dihydro-2H--
pyrano[2,3-b]pyridin-4-amine as a yellow solid.
Step 5:
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-((R)-2'-hydroxy)cyclobuty-
l-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate and
(S)-tert-Butyl6-2,2-difluoropropyl)-2,2-((S)-2'-hydroxy)cyclobutyl-3,4-di-
hydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate
[0344] Di-tert-butyl dicarbonate (0.64 g, 2.9 mmol) was added to a
stirring solution of the
(S)-6-(2,2-difluoropropyl)-2,2-((R)-2'-hydroxy)cyclobutyl-3,4-dihydro-2H--
pyrano[2,3-b]pyridin-4-amine and
(S)-6-(2,2-difluoropropyl)-2,2-((S)-2'-hydroxy)cyclobutyl-3,4-dihydro-2H--
pyrano[2,3-b]pyridin-4-amine mixture (0.64 g, 2.3 mmol),
CH.sub.2Cl.sub.2 (23 mL), and diisopropyethylamine (2.0 mL, 11
mmol) at RT. After 24 h, aqueous 10% Na.sub.2CO.sub.3 was added,
the mixture was stirred vigorously for 1 h, EtOAc was added, the
layers were separated, the organic layer was washed with aqueous
10% Na.sub.2CO.sub.3, brine, dried (Na.sub.2SO.sub.4), filtered,
and the filtrate was concentrated. The residue was purified by
flash chromatography on silica gel (19:1 CH.sub.2Cl.sub.2-methanol)
to afford 0.32 g (37%) of a mixture of
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-((R)-2'-hydroxy)cyclobutyl-3,4-d-
ibydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate and
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-((S)-2'-hydroxy)cyclobutyl-3,4-d-
ihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate as a yellow-brown
solid.
Step 6:
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-cyclobutan-2'-one-3,4-dih-
ydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate
[0345] Dess-Martin periodinane (0.49 g, 1.2 mmol) was added to a
mixture of
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-((R)-2'-hydroxy)cyclobutyl-3,-
4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate and
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-((S)-2'-hydroxycyclobutyl)-3,4-d-
ihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.32 g, 0.83 mmol),
CH.sub.2Cl.sub.2 (8.3 mL), and NaHCO.sub.3 (0.21 g, 2.5 mmol) at
RT. After 2 h, the reaction mixture was purified by flash
chromatography on silica gel (1:1 hexane-ethyl acetate) to afford
0.24 g (75%) of
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-cyclobutan-2'-one-3,4-dihydro-2H-
-pyrano[2,3-b]pyridin-4-ylcarbamate as a colorless solid.
Step 7:
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-(2',2'-difluorocyclobutyl-
)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4ylcarbamate
[0346] Diethylaminosulfur trifluoride (0.41 mL, 3.1 mmol) was added
to a stirring solution of
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-cyclobutan-2'-one-3,4-dihydro-2H-
-pyrano[2,3-b]pyridin-4-ylcarbamate (0.24 g, 0.63 mmol),
CH.sub.2Cl.sub.2 (6.3 mL), and ethanol (7.3 .quadrature.L, 0.13
mmol) at RT. After 24 h, the reaction mixture was added to a
stirring solution of aqueous 10% Na.sub.2CO.sub.3, the mixture was
stirred for 1 h, partitioned between EtOAc and aqueous 10%
Na.sub.2CO.sub.3, the layers were separated, the organic layer was
washed with aqueous 10% Na.sub.2CO.sub.3, brine, dried
(Na.sub.2SO.sub.4), filtered, and the filtrate was concentrated.
The residue was purified by flash chromatography on silica gel (2:1
hexane-ethyl acetate) to give 0.15 g (59%) of of
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-(2',2'-difluorocyclobutyl)-3,4-d-
ihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate as a colorless
solid.
Step 8:
(4S)-6-(2,2-difluoropropyl)-2,2-(2',2'-difluorocyclobutyl)-3,4-dih-
ydro-2H-pyrano[2,3-b]pyridin-4-amine
[0347] Hydrogen chloride (0.93 mL of a 4.0 M solution with
1,4-dioxane, 3.7 mmol) was added to a stirring solution of
(S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-(2',2'-difluorocyclobutyl)-3,4-d-
ihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.15 g, 0.37 mmol)
and CH.sub.2Cl.sub.2 (3.7 mL) at RT. After 24 h, the reaction
mixture was concentrated, the residue was partitioned between
aqueous 10% Na.sub.2CO.sub.3 and ethyl acetate, the layers were
separated, the organic material was washed with aqueous 10%
Na.sub.2CO.sub.3, brine, dried (Na.sub.2SO.sub.4), filtered, and
the filtrate was concentrated to afford
(S)-6-(2,2-difluoropropyl)-2,2-(2',2'-difluorocyclobutyl)-3,4-dihy-
dro-2H-pyrano[2,3-b]pyridin-4-amine as a yellow solid.
Example 16
##STR00035##
[0348]
(4S)-2,2-Spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4-
-dihydro-2H-pyrano(2,3-b)pyridine-4-amine
Step 1: tert-Butyl
allyl((S)-2,2-spirocyclobutyl-6-(3,3,3-trifluoro-1-hydroxy-2-methylpropyl-
)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate
[0349] To a cooled (-78.degree. C.) solution of (S)-tert-butyl
allyl(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4--
yl)carbamate (8.70 g, 21 mmol) in diethylether was added
tert-butyllithium (25 ml, 43 mmol) dropwise. After stirred for 15
min, the fresh distilled 3,3,3-trifluoro-2-methylpropanal (5.8 ml,
53 mmol) was added, and the reaction was stirred for 30 min, and
then quenched with saturated NH4Cl. The resulted mixture was
allowed to warm to RT and extracted with EtOAc (3.times.). The
organic layers were combined, dried over Na2SO4, filtered and
concentrated. The residue was purified on silica gel column to
afford the title compound as a mixture of isomers (4.5 g, 46%
yield) as light yellow oil. MS m/z: 457 (M+1).
Step 2: tert-Butyl
allyl((S)-2,2-spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4--
dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate
[0350] To a cooled (-78.degree. C.) solution of tert-butyl
allyl((S)-2,2-spirocyclobutyl-6-(3,3,3-trifluoro-1-hydroxy-2-methylpropyl-
)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate (1.24 g, 2.7
mmol) in toluene was added (diethylamino)sulfur trifluoride (0.54
ml, 4.1 mmol) via a syringe. The reaction was stirred for 50 min,
then quenched with saturated NH.sub.4Cl (10 ml) and warmed to RT.
The layers were separated. The aqueous layer was extracted with
EtOAc (2.times.20 ml). The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was
purified on a silica gel column (10-15% EtOAc/hexane) to afford the
title compound as a mixture of isomers as colorless oil. MS m/z:
459 (M+1).
Step 3:
(4S)-N-Allyl-2,2-spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpr-
opyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-amine
[0351] To a solution of tert-butyl
allyl((S)-2,2-spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4--
dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate (430 mg, 938
.mu.mol) in MeOH was added hydrogen chloride 4.0 m in 1,4-dioxane
(2.0 ml, 8000 .mu.mol). The reaction was stirred for 2 days (over
the weekend) at RT, then concentrated and neutralized with 10%
Na.sub.2CO.sub.3 and extracted with DCM (3.times.). The organic
layers were combined, dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated and dried in vacuum to afford the title
compound as a mixture of isomers as a light yellow oil. MS+mz: 359
(M+1).
Step 4:
(4S)-2,2-Spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,-
4-dihydro-2H-pyrano(2,3-b)pyridine-4-amine
[0352] The crude product from step 3 above was dissolved in
CH.sub.2Cl.sub.2 (10 ml) to which
1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (439 mg, 2814
.mu.mol) was added. The mixture was purged with N.sub.2 gas for 10
min and tetrakis(triphenylphosphine)palladium (0) (54 mg, 47
.mu.mol) was added. The reaction was heated at 40.degree. C. for 3
h, then cooled and diluted with DCM and washed with 10%
Na.sub.2CO.sub.3 (2.times.). The aqueous layer was back extracted
with EtOAc (2.times.). The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was dried
in vacuum to afford the title compound as mixture of isomers as a
yellow oil. MS m/z: 319 (M+1).
[0353] The following intermeciate materials were made using a
procedure similar to that described in Examples 16, but with
different starting materials.
##STR00036##
Example 17
##STR00037##
[0354]
6-(2',2'-Dimethylpropyl)-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-
-pyrano[2,3-b]pyridin-4-amine
Step 1:
(.+-.)6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,-
3-b]pyridin-4-one
[0355] A mixture of
6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-one
(4.9 g, 18 mmol) and SLECTFLUOR (7.1 g, 20 mmol) in 40 ml of
anhydrous MeOH was heated at 110-130.degree. C. in a presure bottle
for 16 h. The mixture was cooled down and the solids were filtered
off. The filtrate was concentrated to give an oil which was
purified by silica gel chromatography using EtOAc-Hexanes (0-12%)
to give the tile compound as a clear oil which solidified upon
drying.
Step 2:
(.+-.)6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,-
3-b]pyridin-4-yl-(S)-tert-butylsulfinylimine
[0356] A solution of
(.+-.)6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,3-b]pyr-
idin-4-one (3.0 g, 10 mmol) and (S)-2-methylpropane-2-sulfinamide
(2.5 g, 21 mmol) in 5 ml of THF was treated with
tetraethoxytitanium (8.7 ml, 42 mmol) at rt for 18 h. The reaction
mixture was diluted with 100 ml of EtOAc and the resulting solution
was added dropwise to 150 ml of sat. aq. NaHCO.sub.3. White
precipiates formed, and the mixture was stirred at rt vigorously
for 1 h. The EtOAc layer was carefully decanted; the rest of
mixture was filtered through a celite pad with Na.sub.2SO.sub.4.
The celite pad was washed with 150 ml of EtOAc. The filtrates were
combined and the EtOAc layer was separated. All organic layers were
combined, dried (Na.sub.2SO.sub.4) and concentrated to give an oil
that was purified by Isco (0-30% EtOAc in hexanes) to give the
title compound as a yellow foam.
Step 3:
(4R)-6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,3-
-b]pyridin-4-amine
[0357] A solution of
(.+-.)6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,3-b]pyr-
idin-4-yl-(S)-tert-butylsulfinylimine from Step 2 (2.55 g, 6.6
mmol) in 20 ml of THF:H.sub.2O (98:2) at -50.degree. C. was treated
with sodium borohydride (0.74 g, 20 mmol) and the resulting mixture
was stirred and warmed up to rt over 2 h, and then stirred
overnight. The solvents were then removed, The crude esidue was
triturated with DCM, washed with sat. aq. NaHCO.sub.3 (2.times.75
ml), dried over Na.sub.2SO.sub.4 and concentrated to give the title
compound as an oil.
Step 4: (4R)-tert
Butyl6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,3-b]pyri-
din-4-carbamate
[0358] A solution of
(4R)-6-Bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,3-b]pyri-
din-4-amine (1.23 g, 4.3 mmol) in 15 ml of dry DCM was treated with
Boc anhydride (4.3 ml, 4.3 mmol) at rt overnight. The reaction
solvent was removed and the resulting crude residue was purified by
ISCO (0-20% EtOAc on hexanes) to give the titled compound.
Step 5:
(4R)-6-(2'2'-dimethylpropyl)-2,2-spirocyclobutyl-3-fluro-3,4-dihyd-
ro-2H-pyrano[2,3-b]pyridin-4-amine
[0359] To a 50 mL RBF was added (4R)-tert
Butyl6-bromo-2,2-spirocyclobutyl-3-fluro-3,4-dihydro-2H-pyrano[2,3-b]pyri-
din-4-carbamate (580 mg, 1498 .mu.mol), dioxane (10 mL). The
solution was degassed with N.sub.2 for 10 minutes, and Pd catalyst
(53 mg, 75 .mu.mol) was added to the solution. A solution of
neopentylzinc(H) iodide, in THF (8.0 ml, 4000 .mu.mol) was then
added and the reaction mixture was stirred at RT under N.sub.2 for
16 hours. The reaction mixture was quenched with water (20 mL) and
acidified to pH 2 with 1N HCl. The mixture was extracted with EtOAc
(2.times.40 mL). The combined organic layers were washed with brine
and concentrated in vacuo to give a dark brown oil, which was then
treated with MeOH (30 mL) and HCl (4M in dioxane, 10 mL) and
stirred overnight. The material was concentrated in vacuo and taken
up in DCM (5% MeOH was added to improve solubility), and extracted
with 1N HCl (2.times.20 mL). The combined acidic aqueous layers
were washed with DCM (20 mL), neutralized with sat'd NaHCO.sub.3
and extracted with DCM (3.times.20 mL). The combined organic layers
were concentrated in vacuo to give the title compound.
Example 18
##STR00038##
[0360]
(4S)-6-Neopenyl-[(2,2-spirocyclobutyl)-3'-cis-cyano)]-2,3-dihydropy-
rano[2,3-b-]pyridin-4-amine
Step 1: 3-Cyanocyclobutanone
[0361] To a stirred mixture of 3-methylenecyclobutanecarbonitrile
(5.0 g, 54 mmol) and ruthenium trichloride hydrate (0.086 ml, 1.2
mmol) in DCM/MeCN/H.sub.2O (215/215/315 ml) was added sodium meta
periodate (12 ml, 225 mmol) in several portions (30 min.). The
reaction mixture was slowly warmed to RT and stirred in 3 h. The
precipitated solid was filtered off. The filtrate was extracted
with DCM (3.times.); dried over MgSO.sub.4, concentrated and
filtered through a short plug of silical gel, concentrated, to give
the title compound as a light brown oil, which solidified upon
standing at rt.
Step 2:
3-(2-(5-Bromo-2-methoxypyridin-3-yl)-2-oxoethylidene)cyclobutaneca-
rbonitrile
[0362] A mixture of lithium
(Z)-1-(5-bromo-2-methoxypyridin-3-yl)-2-(dimethoxyphosphoryl)ethenolate
(2.0 g, 5.8 mmol) and 3-oxocyclobutanecarbonitrile (1.1 g, 12 mmol)
in p-dioxane (6 ml) was heated at 120.degree. C. by Microwave in 1
h. The mixture was cooled, taken up in H.sub.2O, extracted with
EtOAc (3.times.), dried over MgSO.sub.4, concentrated to provide
the title compound. MS (m+1): 307.0.
Step 3:
6-Bromo-[(2,2-spirocyclobutyl)-3'-cyano)]-2,3-dihydropyrano[2,3-b--
]pyridine-4-one
[0363] A mixture of
3-(2-(5-bromo-2-methoxypyridin-3-yl)-2-oxoethylidene)
cyclobutanecarbonitrile (3.4 g, 11 mmol), sodium iodide (1.8 ml, 44
mmol), and chlorotrimethyl silane (5.6 ml, 44 mmol) in MeCN (40 ml)
was stirred at rt for 24 h, concentrated, taken up in H.sub.2O,
extracted with DCM (3.times.), washed with saturated NH.sub.4Cl,
brine, dried over MgSO.sub.4, concentrated and purified by ISCO
(20% EtOAc/Hexanes) to give the title compound as a yellow
solid.
Step 4:
(4R)-6-Bromo-[(2,2-spirocyclobutyl)-3'-cyano)]-2,3-dihydropyrano[2-
,3-b-]pyridine-4-ol
[0364] To a stirred solution of (S)-2-methyl-CBS-oxazaborolidine
(1M in toluene; 1.0 ml, 1.0 mmol) in toluene (5 ml) was added a
solution of borane-methyl sulfide complex (0.5 ml, 5 mmol) in
toluene (20 ml) and a solution of
6-bromo-[(2,2-spirocyclobutyl)-3'-cyano)]-2,3-dihydropyrano[2,3-b-]pyridi-
ne-4-one (1.40 g, 5 mmol) in toluene (20 ml) in 30 min at 0.degree.
C. The reaction mixture was stirred for another 15 min. then slowly
quenched with 10% aq. HCl, extracted with EtOAc (3.times.), washed
with NaHCO.sub.3, brine, dried over MgSO.sub.4, concentrated to
give the title compound as a light yellow solid. MS (m+1):
296.1
Step 5:
(4R)-6-Bromo-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3-
'-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine
[0365] To a stirred mixture of
(4R)-6-bromo-[(2,2-spirocyclobutyl)-3'-cyano)]-2,3-dihydropyrano[2,3-b-]p-
yridine-4-ol (5.7 g, 19 mmol) and 1H-imidazole (22 ml, 193 mmol) in
DMF (70 ml) was added tert-butylchlorodimethylsilane (15 g, 97
mmol). The reaction mixture was stirred at rt in 24 h, added water,
extracted with ether (3.times.), dried over MgSO.sub.4,
concentrated and purified by ISCO (15% EtOAc/Hexanes) to give the
title compound. MS (m+1): 410.4.
Step 6:
(4R)-6-(2'2-dimethylpropyl)-4-tert-butyldimethylsilyloxo-[(2,2-spi-
rocyclobutyl)-3'-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine
[0366] To a stirred solution of neopentylmagnesium chloride (1M,15
ml, 15 mmol) at 0.degree. C. was added dropwise a solution of
zinc(II) chloride (8 ml, 8 mmol). The mixture was gradually warmed
to rt in 30 min. PdCl.sub.2(dppf).sub.2 (0.2 g, 0.2 mmol) and a
solution of
(4R)-6-bromo-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3'-cyano-
)]-2,3-dihydropyrano[2,3-b-]pyridine (1.56 g, 4 mmol) in THF (20
ml) were successively added to the mixture. The reaction mixture
was stirred at 40.degree. C. overnight, then cooled, quenched with
saturated NH.sub.4Cl, extracted with EtOAc, dried over MgSO.sub.4,
concentrated to provide the title compound. MS (m+1): 401.6.
Step 7:
(4R)-6-Neopenyl-[(2,2-spirocyclobutyl)-3'-cis-cyano)]-2,3-dihydrop-
yrano[2,3-b-]pyridine-4-ol and
(4R)-6-neopenyl-[(2,2-spirocyclobutyl)-3'-trans-cyano)]-2,3-dihydropyrano-
[2,3-b]pyridine-4-ol
[0367] To a stirred solution of
(4R)-6-neopentyl-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3'-c-
yano)]-2,3-dihydropyrano[2,3-b-]pyridine (1.5 g, 4 mmol) in THF (10
ml) was added tetrabutylammonium fluoride, 1.0M in THF (7 ml, 7
mmol). The reaction mixture was stirred in 2 h, quenched with
H.sub.2O, extracted with EtOAc, dried over MgSO.sub.4, concentrated
and purified by ISCO (40% EtOAc/Hexanes with 120 g column) to
separate the cis- and trans-isomers of the title compound. MS
(m+1): 287.4.
Step 8:
(4S)-4-Azido-6-neopenyl-[(2,2-spirocyclobutyl)-3'-cis-cyano)]-2,3--
dihydropyrano[2,3-b]pyridine
[0368] To a stirred solution of
(4R)-6-neopenyl-[(2,2-spirocyclobutyl)-3'-cis-cyano)]-2,3-dihydropyrano[2-
,3-b-]pyridine-4-ol (1.05 g, 3.67 mmol) in toluene (30 ml) was
added DPPA (1.03 ml, 4.77 mmol) dropwise. After stirring for 15
min., DBU (0.713 ml, 4.77 mmol) was slowly added, and the reaction
mixture was stirred at RT for 16 h. H.sub.2O was added and the
mixture was extracted with EtOAc (3.times.), washed with brine,
dried over MgSO.sub.4, concentrated to give the title compound as a
brown oil. MS (m+1): 312.4.
Step 9:
(4S)-6-Neopenyl-[(2,2-spirocyclobutyl)-3'-cis-cyano)]-2,3-dihydrop-
yrano[2,3-b-]pyridin-4-amine
[0369] A mixture of
(4S)-4-azido-6-neopenyl-[(2,2-spirocyclobutyl)-3'-cis-cyano)]-2,3-dihydro-
pyrano[2,3-b-]pyridine (3 g, 10 mmol) and triphenylphosphine (3 g,
10 mmol) in THF (20 ml) was stirred at RT in 2 h, 3 ml of H.sub.2O
was added and heated at 80.degree. C. in 4 h. 40 ml of 10% aq. HCl
was added and the mixture was heated for 10 min. at 80.degree. C.,
then cooled and extracted with toluene, (discarded). The acidic
aqueous layer was neutralized with solid Na.sub.2CO.sub.3,
extracted with DCM (3.times.), dried over MgSO.sub.4, purified by
ISCO (3% MeOH/DCM) to give the title compound as a yellow foam. MS
(m+1): 286.4.
[0370] The following intermeciate materials were made using a
procedure similar to that described in Examples 18, but with
different starting materials.
##STR00039##
Example 19
##STR00040##
[0371]
(S)-6-Bromo-N.sup.8-ethyl-2,2,-spirocyclobutyl-3,4-dihydro-2H-chrom-
ene-4,8-diamine
Step 1: 1-(3-amino-5-bromo-2-hydroxyphenyl)ethanone
[0372] A mixture of 1-(5-bromo-2-hydroxy-3-nitrophenyl)ethanone (25
g, 96 mmol), iron (27 g, 481 mmol), and NH.sub.4Cl (5.1 g, 96 mmol)
in EtOH/H.sub.2O (5:1, 300 ml) was heated at reflux in 2 h, the
mixture was cooled filtered the solid, the filtrate was
concentrated, taken up in H.sub.2O, extracted with DCM (3.times.),
dried over MgSO.sub.4, concentrated and purified by ISCO (10%
EtOAc/Hexanes) to give the title compound as a yellow solid. MS
(m+2): 232.1.
Step 2:
8-Amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one
[0373] A mixture of 1-(3-amino-5-bromo-2-hydroxyphenyl)ethanone
(4.5 g, 20 mmol), cyclobutanone (3 ml, 39 mmol), and pyrrolidine (5
ml, 59 mmol) in p-dioxane (80 ml) was heated at 65.degree. C. for
24 h. The mixture was cooled, taken up in dilute acid, stirred,
extracted with EtOAc (3.times.), dried over MgSO.sub.4,
concentrated and purified by ISCO (0-20% in 30 min.) to give the
title compound as an orange solid. MS (m+2): 284.1.
Step 3:
(4R)-8-Amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-ol
[0374] To a stirred solution of (s)-2-methyl-CBS-oxazaborolidine,
1M in toluene (1 ml, 1 mmol) in toluene (2 ml) was added a solution
of borane-methyl sulfide complex (5 ml, 11 mmol) in toluene (20 ml)
followed by addition of a solution of
8-amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one (3 g,
11 mmol) in toluene (40 ml) dropwise. After the reaction was
complete as monitored by TLC, it was quenched with 10% aq. HCl (40
ml), stirred for 15 min., extracted with EtOAc (3.times.), washed
with brine, dried over MgSO.sub.4, filtered and concentrated to
give the title compound as a purple foam. MS (m+1): 285.2.
Step 4:
(4R)-8-Amino-6-bromo-4-tertbulyldimethylsilyloxo-2,2-spirocyclobut-
yl-2,3-dihydrochromene
[0375] A mixture of
8-amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-ol (3.2 g,
11 mmol) and imidazole (1 ml, 12 mmol) in DCM (30 ml) was added
tert-butylchlorodimethylsilane (2 g, 12 mmol). The mixture was
stirred for 3 h, then H.sub.2O was added and the layers were
separated, dried over MgSO.sub.4, concentrated and the crude was
purified by ISCO (5% EtOAc/Hexanes) to give the title compound as a
colorless oil. MS (m+1): 399.4.
Step 5:
(4R)-8-ethylamino-6-bromo-4-tertbutyidimethylsilyloxo-2,2-spirocyc-
lobutyl-2,3-dihydrochromene
[0376] A mixture of
(4R)-8-amino-6-bromo-4-tertbutyldimethylsilyloxo-2,2-spirocyclobutyl-2,3--
dihydrochromene (2 g, 5 mmol), acetaldehyde (0.3 ml, 5 mmol), and
trimethyl orthoformate (4 ml, 40 mmol) in DCE (20 ml) was stirred
at RT in 30 min. Sodium triacetoxyborohydride (5 g, 25 mmol) was
added and stirred in 3 h, quenched with diluted aq. HCl, extracted
with DCM (3.times.), dried over MgSO.sub.4, concentrated and
purified by ISCO (5% EtOAc/Hexanes) to give the title compound as a
light yellow oil. MS (m+1): 428.4.
Step 6:
(4R)-6-Bromo-8-(ethylamino)-2,2-spirocyclobutyl-3,4-dihydro-2H-chr-
omen-4-ol
[0377] A mixture of
(4R)-8-ethylamino-6-bromo-4-tertbutyldimethylsilyloxo-2,2-spirocyclobutyl-
-2,3-dihydrochromene (0.900 g, 2.2 mmol) [and tetrabutylammonium
fluoride (2.6 ml, 2.6 mmol)] in THF (15 ml) was added
tetrabutylammonium fluoride (2.6 ml, 2.6 mmol). The reaction
mixture was stirred at rt in 2 h. H.sub.2O was added and the
mixture was extracted with EtOAc (3.times.), dried over MgSO.sub.4,
concentrated to give the title compound as a brown oil. MS (m+1):
304.4.
Step 7:
(S)-6-Bromo-N.sup.8-ethyl-2,2,-spirocyclobutyl-3,4-dihydro-2H-chro-
mene-4,8-diamine
[0378] The title compound was obtained, as a white foam, by a
method analogous to that described in Steps 6-8 of Example 6 above.
MS (m+1): 312.2.
Example 20
##STR00041##
[0379]
(4S)-[(2,2-Spirocyclobutyl-3'(trans)-hydroxyl)]-6-neopentyl-3,4-dih-
ydro-2H-chromen-4-amine and
(4S)-[(2,2-Spirocyclobutyl-3'(cis)-hydroxyl)]-6-neopentyl-3,4-dihydro-2H--
chromen-4-amine
Step 1: 2,2-Dichloro-3-oxocyclobutyl pivalate
[0380] To a stirred mixture of vinyl pivalate (30 g, 234 mmol) and
zinc (31 g, 468 mmol) in ether (300 ml) was added a solution of
2,2,2-trichloroacetyl chloride (55 g, 304 mmol) in ether (300 ml)
dropwise (2-3 h) in a water bath. (Note: fast addition causes the
reaction temp.to elevate) while maintaining the reaction
temperature between 15-30.degree. C. After the reaction was done
(stained with KMnO.sub.4 solution), it was filtered through Celite.
The filtrate was washed with cold water, brine, dried over
MgSO.sub.4 and concentrated to give the title compound as an orange
solid.
Step 2: 3-Oxocyclobutyl pivalate
[0381] To a stirred suspension of zinc dust (103 g, 1568 mmol) in
HOAc (200 ml) was added a solution of 2,2-dichloro-3-oxocyclobutyl
pivalate (75 g, 314 mmol) in HOAc (400 ml) dropwise in an ice bath.
The reaction mixture was stirred for 1 h, filtered the solid
through celite and washed with DCM. The DCM layer was washed with
H.sub.2O, NaHCO.sub.3, brine, dried over MgSO.sub.4, filterd and
concentrated. The crude material was purified by ISCO (10%
EtOAc/Hexanes) to give the title compound as a light yellow
oil.
Step 3: 3-Hydroxylcyclobutyl pivalate
[0382] To a stirred solution of 3-oxocyclobutyl pivalate (15.1 g,
88.7 mmol) in ethanol (100 ml) at 0.degree. C. was added sodium
borohydride (4.69 ml, 133 mmol) in several portions. The reaction
was stirred for 30 min, slowly quenched with 10% aqueous HCl and
concentrated to remove ethanol. The solution was taken up with more
10% HCl, extracted with DCM (3.times.), washed with brine, dried
over MgSO.sub.4 and concentrated to give the title compound as a
light yellow oil.
Step 4: 3-(tert-Butyldimethylsilyloxy)cyclobutyl pivalate
[0383] To a stirred mixture of 3-hydroxycyclobutyl pivalate (16.60
g, 96.4 mmol) and diea (25.2 ml, 145 mmol) in DCM (100 ml) at
0.degree. C. was added tert-butyldimethylsilyl triflate (31.0 ml,
135 mmol) dropwise. The reaction was stirred for 2 h, then quenched
with H.sub.2O. The layers were separated, and the organic layer was
washed with saturated NaHCO.sub.3, brine, dried over MgSO.sub.4 and
concentrated to give the title compound as a light brown oil.
Step 5: 3-(tert-butyldimethylsilyloxy)cyclobutanol
[0384] To a stirred solution of
3-(tert-butyldimethylsilyloxy)cyclobutyl pivalate (4.32 g, 15 mmol)
in THF (20 ml) at 0.degree. C. was added diisobutylaluminum
hydride, 1.0 m solution in hexanes (48 ml, 48 mmol) dropwise. The
reaction was stirred in 1 h, then slowly quenched with Rochelle's
salt. The quenched mixture was stirred and layers were separated.
The organic layer was dried over MgSO.sub.4 and concentrated to
give the title compound as a colorless oil.
Step 6: 3-(tert-butyldimethylsilyloxy)cyclobutanone
[0385] A mixture of 3-(tert-butyldimethylsilyloxy)cyclobutanol
(2.59 g, 13 mmol), sodium bicarbonate (3 ml, 38 mmol), and Reactant
1[?] (7 g, 15 mmol) in DCM (40 ml) was stirred at RT in 4 h, the
solid was filtered; the filtrated was purified by ISCO (5%
EtOAc/Hexanes) to give the title compound as a colorless oil.
Step 7:
(4S)-[(2,2-Spirocyclobutyl-3'(trans)-hydroxyl)]-6-neopentyl-3,4-di-
hydro-2H-chromen-4-amine and
(4S)-[(2,2-Spirocyclobutyl-3'(cis)-hydroxyl)]-6-neopentyl-3,4-dihydro-2H--
chromen-4amine
[0386] The title compounds were obtained, by a method analogous to
that described in Steps 6-8 of Example 6 above, after separation of
the cis- and trans-isomers by reverse phase HPLC. MS (m+1):
261.2.
Example 21
##STR00042##
[0387]
(2R,3,S)-3-([1,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-4-(3,5-difluor-
ophenyl)-1-((R)-2,2-spirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-
-b]pyridine-4-ylamino)butan-2-ol.
Step 1: 2-Chloropyrimidin-4-amine
[0388] To a suspension of 2,4-dichloropyrimidine (2.0 g, 13 mmol)
in isopropanol (20 mL) was added ammonium hydroxide 28-30% (50 mL,
1385 mmol). The suspension went into solution immediately. The
resulting solution was heated at 100.degree. C. in a sealed tube
for 18 h. The mixture was brought to RT, extracted with DCM and the
combined organics were dried over MgSO.sub.4, filtered, and
concentrated to afford an off-white solid as
2-chloropyrimidin-4-amine (1.7 g, 57% yield). MS m/z: 130.0
(M+1).
Step 2: 1-(3-Chloropyrazin-2-yl)hydrazine
[0389] 2,3-Dichloropyrazine (2 mL, 13 mmol) was dissolved in 95%
ethanol (4 mL) and to this was added, dropwise and with stirring,
hydrazine anhydrous (2 mL, 67 mmol). During the addition of the
hydrazine the solution became warm and yellowish. Following cooling
of this mixture in an ice bath, the resulting material was isolated
by filtration, washed with cold aqueous 95% ethanol to riled
1-(3-chloropyrazin-2-yl)hydrazine (1.42 g, 73% yield) as white
crystals. No further purification was done. MS m/z: 145.0
(M+1).
Step 3: 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine
##STR00043##
[0391] A mixture of 1-(3-chloropyrazin-2-yl)hydrazine (0.90 g, 62
mmol), triethyl orthoformate (2.3 mL), 14 mmol), and dry xylene (15
mL) was refluxed with stirring for 2 h. The mixture was brought to
RT, diethyl ether was added and the suspension was filtered. The
solid collected was washed with diethyl ether to afford
8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (0.60 g, 62% yield). MS
m/z: 155.0 (M+1).
Step 4: (2R,3,S)-3-([1
2,4]triazolo[4,3-a]pyrazin-8-ylamino)-4-(3,5-difluorophenyl)-1-((R)-2,2-s-
pirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ylamino-
)butan-2-ol.
[0392] A mixutire of
##STR00044##
(0.070 g, 0.13 mmol), 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine
(0.020 g, 0.13 mmol) and sodium carbonate monohydrate (0.016 g,
0.13 mmol) in ethanol (2 mL) and dimethylformamide (2 mL) was
heated at 45.degree. C. for 4 days. The mixture was brought to RT,
concentrated, and the residue was dissolved in ethyl acetate. The
organic phase was washed with water, brine, dried over MgSO.sub.4,
filtered, concentrated, and purified by HPLC to afford
(2R,3,S)-3-([1,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-4-(3,5-difluoropheny-
l)-1-((R)-2,2-spirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyr-
idine-4-ylamino)butan-2-ol as a light yellow solid. MS m/z: 577.8
(M+1).
Example 22
##STR00045##
[0393]
(2R,3S)-3-([1,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-1-((R)-6-bromo--
2,2-spirocyclobutanechroman-4-ylamino)-4-phenylbutan-2-ol.
[0394] To a solution of 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine
(0.032 g, 0.21 mmol) and sodium carbonate monohydrate (0.026 g,
0.21 mmol) in ethanol (2 mL) and dimethylformamide was added the
chroman-amine
##STR00046##
(0.89 g, 0.21 mmol). The resulting mixture was stirred and heated
at 60.degree. C. for 17 h. The mixture was concentrated and the
residue was dissolved in ethyl acetate, washed with water, brine,
dried over Na.sub.2SO.sub.4, filtered, concentrated, and purified
by HPLC to afford a light yellow solid as
2R,3S)-3-([1,2,4]triazolo[4,3-a]pyrazin-8-ylamino)-1-((R)-6-bromo-2,2-spi-
rocyclobutanechroman-4-ylamino)-4-phenylbutan-2-ol. MS m/z: 551.1
(M+1).
Example 23
##STR00047##
[0395]
(2R,3S)-1-((R)-6-ethyl-2,2-spirocyclopentanechroman-4-ylamino)-4-ph-
enyl-3-(2-phenylpyrimidin-4-ylamino)butan-2-ol.
Step 1:
(2R,3S)-3-(2-chloropyrimidine-4-ylamino)-1-((R)-6-ethyl-2,2-spiroc-
yclopentanechroman-4-ylamino)-4-phenylbutan-2-ol.
[0396] A solution of 2,4-dichloropyrimidine (0.050 g, 0.34 mmol),
ethylchroman-amine
##STR00048##
(0.13 g, 0.34 mmol), and sodium carbonate monohydrate (0.036 mg,
0.34 mmol) in isopropanol (3 mL) and dimethylformamide (3 mL) was
heated in a sealed tube for 17 h. The mixture was brought to room
temperature, concentrated and the residue was dissolved in ethyl
acetate, washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to afford
(2R,3S)-3-(2-chloropyrimidine-4-ylamino)-1-((R)-6-ethyl-2,2-spiroc-
yclopentanechroman-4-ylamino)-4-phenylbutan-2-ol (0.13 g, 76%
yield). MS m/z: 507.2 (M+1).
Step 2:
(2R,3S)-1-((R)-6-ethyl-2,2-spirocyclopentanechroman-4-ylamino)-4-p-
henyl-3-(2-phenylpyrimidin-4-ylamino)butan-2-ol.
[0397] A mixture of phenylboronic acid (0.063 g, 0.52 mmol),
(2R,3S)-3-(2-chloropyrimidine-4-ylamino)-1-((R)-6-ethyl-2,2-spirocyclopen-
tanechroman-4-ylamino)-4-phenylbutan-2-ol (0.13 g, 0.26 mmol),
PdCl.sub.2(dppf).sub.2 (0.021 g, 0.026 mmol), and sodium carbonate
monohydrate (0.097 g, 0.78 mmol) in dimethylformamide was heated to
reflux for 3 h and brought to room temperature. The mixture was
filtered through celite, concentrated, and purified by HPLC to
afford a white solid as
(2R,3S)-1-((R)-6-ethyl-2,2-spirocyclopentanechroman-4-ylamino)-4-
-phenyl-3-(2-phenylpyrimidin-4-ylamino)butan-2-ol MS m/z: 549.4
(M+1).
[0398] The following examples in Table I were prepared by Methods A
(Scheme 7), B (Scheme 8) or C (Scheme 9) and/or steps analogous to
those described in Examples 6, 9, 11 and 21-23 above.
TABLE-US-00001 TABLE 1 Enzyme Cell Mass Data Data Method Ex. found
IC.sub.50 IC.sub.50 of No. Compound Name (M + H).sup.+ (uM) (uM)
making 24 (2R,3S)-3-((2-chloro-4- 572.1 +++++ ++++ B
pyrimidinyl)amino)-4-(3,5- difluorophenyl)-1-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'- dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'- yl)amino)-2-butanol 21
(2R,3S)-4-(3,5-difluorophenyl)-1- 577.8 ++++ +++++ A
(((4'S)-6'-(2,2-dimethylpropyl)-
3',4'-dihydrospiro[cyclobutane-1,2'- pyrano[2,3-b]pyridin]-4'-
yl)amino)-3-([1,2,4]triazolo[4,3- a]pyrazin-8-ylamino)-2-butanol 25
(2R,3S)-4-(3,5-difluorophenyl)-1- 538.2 ++++ +++ B
(((4'S)-6'-(2,2-dimethylpropyl)-
3',4'-dihydrospiro[cyclobutane-1,2'- pyrano[2,3-b]pyridin]-4'-
yl)amino)-3-(2-pyrimidinylamino)- 2-butanol 26
(2R,3S)-4-(3,5-difluorophenyl)-1- 554.2 +++ + B
(((4'S)-6'-(2,2-dimethylpropyl)-
3',4'-dihydrospiro[cyclobutane-1,2'- pyrano[2,3-b]pyridin]-4'-
yl)amino)-3-((2- fluorophenyl)amino)-2-butanol 27
3-((2S,3R)-4-(((4S)-6-ethyl-3,4- 500.1 +++ ++++ B
dihydrospiro[chromene-2,1'- cyclobutan]-4-yl)amino)-2-((2-
fluorophenyl)amino)-3- hydroxybutyl)benzonitrile 28
(2R,3S)-3-((6-chloro-4- 554.2 +++ + A
pyrimidinyl)amino)-1-(((4'S)-6'-(2,2- dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-4- (4-fluorophenyl)-2-butanol 29
(2R,3S)-3-((2-chloro-4- 554.2 +++ + A
pyrimidinyl)amino)-1-(((4'S)-6'-(2,2- dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-4- (4-fluorophenyl)-2-butanol 30
(2R,3S)-1-(((4'S)-6'-(2,2- 576.2 ++ + A dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-4-
(4-fluorophenyl)-3-(thieno[3,2- d]pyrimidin-4-ylamino)-2-butanol 31
(2R,3S)-1-(((4S)-6-ethyl-3,4- 475.3 ++ + B
dihydrospiro[chromene-2,1'- cyclobutan]-4-yl)amino)-3-((2-
fluorophenyl)amino)-4-phenyl-2- butanol 32
(2R,3S)-1-(((4S)-6-ethyl-3,4- 489.2 ++ + B
dihydrospiro[chromene-2,1'- cyclopentan]-4-yl)amino)-3-((2-
fluorophenyl)amino)-4-phenyl-2- butanol 33
(2R,3S)-1-((S)-6-ethyl-2,2- 527.2 + + A
spirocyclobutyl-chroman-4-ylamino)- 4-phenyl-3-(4-
(trifluoromethyl)pyrimidin-2- ylamino)butan-2-ol 34
(2R,3S)-3-((6-chloro-2-(methylthio)-4- 600.1 ++ + A
pyrimidinyl)amino)-1-(((4'S)-6'-(2,2- dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-4- (4-fluorophenyl)-2-butanol 35
(2R,3S)-1-(((4'S)-6'-(2,2- 576.2 + ++++ A dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-4-
(4-fluorophenyl)-3-(thieno[2,3- d]pyrimidin-4-ylamino)-2-butanol 22
(2R,3S)-1-(((4S)-6-bromo-3,4- 551.1 + ++ B
dihydrospiro[chromene-2,1'- cyclobutan]-4-yl)amino)-4-phenyl-3-
([1,2,4]triazolo[4,3-a]pyrazin-8- ylamino)-2-butanol 36
(2R,3S)-3-(1,3-benzoxazol-2- 498.2 + +++ A
ylamino)-1-(((4S)-6-ethyl-3,4- dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-4-phenyl-2- butanol 37
(2R,3S)-1-((S)-6-ethyl-2,2- 487.5 + ++ A
spirocyclobutyl-chroman-4-ylamino)- 4-phenyl-3-(4-ethyl
pyrimidin-2- ylamino)butan-2-ol 38 (2R,3S)-1-((S)-6-ethyl-2,2-
459.2 + + A spirocyclobutyl-chroman-4-ylamino)-
4-phenyl-3-(pyrimidin-2- ylamino)butan-2-ol 39
(2R,3S)-3-((6-chloro-3- 493.3 + + A
pyridazinyl)amino)-1-(((4S)-6-ethyl-
3,4-dihydrospiro[chromene-2,1'- cyclobutan]-4-yl)amino)-4-phenyl-2-
butanol 40 (2R,3S)-1-(((4S)-6-ethyl-3,4- 473.4 + C
dihydrospiro[chromene-2,1'- cyclopentan]-4-yl)amino)-4-phenyl-3-
(2-pyrazinylamino)-2-butanol 41 (2S,3S)-1-(((4'S)-6'-(2,2- 518.3 +
+ B dimethylpropyl)-3',4'- dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-3-
((2-fluorophenyl)amino)-4-phenyl-2- butanol 42
(2R,3S)-3-(1,3-benzothiazol-2- 514.3 + A
ylamino)-1-(((4S)-6-ethyl-3,4- dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-4-phenyl-2- butanol 43
(2R,3S)-1-(((4S)-6-ethyl-3,4- 458.4 + + B
dihydrospiro[chromene-2,1'- cyclobutan]-4-yl)amino)-4-phenyl-3-
(3-pyridinylamino)-2-butanol 44 (2R,3S)-1-(((4S)-6-ethyl-3,4- 458.4
+++ B dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-4-phenyl-3- (4-pyridinylamino)-2-butanol 45
3-(((1S,2R)-3-(((4'S)-6'-(2,2- 566.0 +++++ ++++
dimethylpropyl)-3',4'- dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-1- ((3-fluorophenyl)methyl)-2-
hydroxypropyl)amino)-4-(ethyloxy)-3- cyclobutene-1,2-dione The
following key will help to appreciate the data provided in Table I:
+ designates an IC.sub.50 value in the range from 10 uM-25 uM; ++
designates an IC.sub.50 value in the range from 5 uM-10 uM; +++
designates an IC.sub.50 value in the range from 1.0 uM-5 uM; ++++
designates an IC.sub.50 value in the range from 100 nM-1.0 uM; and
+++++ designates an IC.sub.50 value of below 100 nM
[0399] The following examples provide a further understanding and
appreciation of compounds of the present invention.
[0400] The present invention also provides methods for making
compounds of Formulas I-II. In another embodiment of the invention,
there is provided a method of making a compound of Formula I or II,
the method comprising the step of reacting a compound 30
##STR00049##
wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, X and ring Z are as defined herein, with a
compound having the structure R.sup.1-halo, wherein R.sup.1 is as
defined herein and "halo" is a halogen group, generally a chlorine,
bromine or iodine, to make a compound of Formulas I or II.
[0401] As can be appreciated by the skilled artisan, the above
synthetic schemes and representative examples are not intended to
comprise a comprehensive list of all means by which the compounds
described and claimed in this application may be synthesized.
Further methods will be evident to those of ordinary skill in the
art. Additionally, the various synthetic steps described above may
be performed in an alternate sequence or order to give the desired
compounds.
[0402] For example, in these procedures, the steps may be preceded,
or followed, by additional protection/deprotection steps as
necessary. Particularly, if one or more functional groups, for
example carboxy, hydroxy, amino, or mercapto groups, are or need to
be protected in preparing the compounds of the invention, because
they are not intended to take part in a specific reaction or
chemical transformation, various known conventional protecting
groups may be used. For example, protecting groups typically
utilized in the synthesis of natural and synthetic compounds,
including peptides, nucleic acids, derivatives thereof and sugars,
having multiple reactive centers, chiral centers and other sites
potentially susceptible to the reaction reagents and/or conditions,
may be used.
[0403] The protecting groups may already be present in precursors
and should protect the functional groups concerned against unwanted
secondary reactions, such as acylations, etherifications,
esterifications, oxidations, solvolysis, and similar reactions. It
is a characteristic of protecting groups that they readily lend
themselves, i.e. without undesired secondary reactions, to removal,
typically accomplished by solvolysis, reduction, photolysis or
other methods of removal such as by enzyme activity, under
conditions analogous to physiological conditions. It should also be
appreciated that the protecting groups should not be present in the
end-products. The specialist knows, or can easily establish, which
protecting groups are suitable with the reactions described herein.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the inhibitor compounds described herein are known in the art and
include, for example, those such as described in R. Larock,
Comprehensive Organic Transformations, VCH Publishers (1989); T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3.sup.rd edition, John Wiley and Sons (1999); L. Fieser and M.
Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of
Heterocyclic Chemistry, 2.sup.nd edition (2001); M. Bodanszky, A.
Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag,
Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the
Alumino- and Borohydrides in Organic Synthesis, 2.sup.nd edition,
Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of
Reagents for Organic Synthesis, John Wiley and Sons (1995).
[0404] Salts, including pharmaceutically acceptable salts, of a
compound of the invention having a salt-forming group may be
prepared in a conventional manner or manner known to persons
skilled in the art. For example, acid addition salts of compounds
of the invention may be obtained by treatment with an acid or with
a suitable anion exchange reagent. A salt with two acid molecules
(for example a dihalogenide) may also be converted into a salt with
one acid molecule per compound (for example a monohalogenide); this
may be done by heating to a melt, or for example by heating as a
solid under a high vacuum at elevated temperature, for example from
50.degree. C. to 170.degree. C., one molecule of the acid being
expelled per molecule of the compound.
[0405] Acid salts can usually be converted to free-base compounds,
e.g. by treating the salt with suitable basic agents, for example
with alkali metal carbonates, alkali metal hydrogen carbonates, or
alkali metal hydroxides, typically potassium carbonate or sodium
hydroxide. Exemplary salt forms and their preparation are described
herein in the Definition section of the application.
[0406] All synthetic procedures described herein can be carried out
under known reaction conditions, advantageously under those
described herein, either in the absence or in the presence
(usually) of solvents or diluents. As appreciated by those of
ordinary skill in the art, the solvents should be inert with
respect to, and should be able to dissolve, the starting materials
and other reagents used. Solvents should be able to partially or
wholly solubilize the reactants in the absence or presence of
catalysts, condensing agents or neutralizing agents, for example
ion exchangers, typically cation exchangers for example in the
H.sup.+ form. The ability of the solvent to allow and/or influence
the progress or rate of the reaction is generally dependant on the
type and properties of the solvent(s), the reaction conditions
including temperature, pressure, atmospheric conditions such as in
an inert atmosphere under argon or nitrogen, and concentration, and
of the reactants themselves.
[0407] Suitable solvents for conducting reactions to synthesize
compounds of the invention include, without limitation, water;
esters, including lower alkyl-lower alkanoates, e.g., EtOAc; ethers
including aliphatic ethers, e.g., Et.sub.2O and ethylene glycol
dimethylether or cyclic ethers, e.g., THF; liquid aromatic
hydrocarbons, including benzene, toluene and xylene; alcohols,
including MeOH, EtOH, 1-propanol, IPOH, n- and t-butanol; nitriles
including CH.sub.3CN; halogenated hydrocarbons, including
CH.sub.2Cl.sub.2, CHCl.sub.3 and CCl.sub.4; acid amides including
DMF; sulfoxides, including DMSO; bases, including heterocyclic
nitrogen bases, e.g. pyridine; carboxylic acids, including lower
alkanecarboxylic acids, e.g., AcOH; inorganic acids including HCl,
HBr, HF, H.sub.2SO.sub.4 and the like; carboxylic acid anhydrides,
including lower alkane acid anhydrides, e.g., acetic anhydride;
cyclic, linear, or branched hydrocarbons, including cyclohexane,
hexane, pentane, isopentane and the like, and mixtures of these
solvents, such as purely organic solvent combinations, or
water-containing solvent combinations e.g., aqueous solutions.
These solvents and solvent mixtures may also be used in
"working-up" the reaction as well as in processing the reaction
and/or isolating the reaction product(s), such as in
chromatography.
[0408] Purification methods are known in the art and include, for
example, crystallization, chromatography (liquid and gas phase, and
the like), extraction, distillation, trituration, reverse phase
HPLC and the like. Reactions conditions such as temperature,
duration, pressure, and atmosphere (inert gas, ambient) are known
in the art and may be adjusted as appropriate for the reaction.
[0409] The invention further encompasses "intermediate" compounds,
including structures produced from the synthetic procedures
described, whether isolated or generated in-situ and not isolated,
prior to obtaining the finally desired compound. Structures
resulting from carrying out steps from a transient starting
material, structures resulting from divergence from the described
method(s) at any stage, and structures forming starting materials
under the reaction conditions are all "intermediates" included in
the invention. Further, structures produced by using starting
materials in the form of a reactive derivative or salt, or produced
by a compound obtainable by means of the process according to the
invention and structures resulting from processing the compounds of
the invention in situ are also within the scope of the
invention.
[0410] New starting materials and/or intermediates, as well as
processes for the preparation thereof, are likewise the subject of
this invention. In select embodiments, such starting materials are
used and reaction conditions so selected as to obtain the desired
compound(s).
[0411] Starting materials of the invention, are either known,
commercially available, or can be synthesized in analogy to or
according to methods that are known in the art. Many starting
materials may be prepared according to known processes and, in
particular, can be prepared using processes described in the
examples. In synthesizing starting materials, functional groups may
be protected with suitable protecting groups when necessary.
Protecting groups, their introduction and removal are described
above.
[0412] Compounds of the present invention can possess, in general,
one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or non-racemic mixtures thereof. The optical isomers can be
obtained by resolution of the racemic mixtures according to
conventional processes, e.g., by formation of diastereoisomeric
salts, by treatment with an optically active acid or base. Examples
of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and
then separation of the mixture of diastereoisomers by
crystallization followed by liberation of the optically active
bases from these salts. A different process for separation of
optical isomers involves the use of a chiral chromatography column
optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent
diastereoisomeric molecules by reacting compounds of the invention
with an optically pure acid in an activated form or an optically
pure isocyanate. The synthesized diastereoisomers can be separated
by conventional means such as chromatography, distillation,
crystallization or sublimation, and then hydrolyzed to deliver the
enantiomerically pure compound. The optically active compounds of
the invention can likewise be obtained by using optically active
starting materials. These isomers may be in the form of a free
acid, a free base, an ester or a salt. All such isomeric forms of
such compounds are expressly included in the present invention.
[0413] The compounds of this invention may also be represented in
multiple tautomeric forms. The compounds may also occur in cis- or
trans- or E- or Z-double bond isomeric forms. The invention
expressly includes all tautomeric forms of the compounds described
herein.
[0414] All crystal forms of the compounds described herein are
expressly included in the present invention.
[0415] Substituents on ring moieties (e.g., phenyl, thienyl, etc.)
may be attached to specific atoms, whereby they are intended to be
fixed to that atom, or they may be drawn unattached to a specific
atom, whereby they are intended to be attached at any available
atom that is not already substituted by an atom other than H
(hydrogen). For example, the R.sup.12 substituent is drawn
unattached to any specific atom of ring Z.sup.2, and therefore each
of the n number of R.sup.12 substituents may be attached to any
atom of Z.sup.2.
[0416] The present invention also includes isotopically-labelled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.16O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl.
[0417] Compounds of the present invention that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically-labelled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detection. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
this invention can generally be prepared by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
Biological Evaluation
[0418] The compounds of the invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. Such modifications may increase biological penetration
into a given biological compartment (e.g., blood, lymphatic system,
central nervous system), increase oral availability, increase
solubility to allow administration by injection, alter metabolism
and alter rate of excretion. By way of example, a compound of the
invention may be modified to incorporate a hydrophobic group or
"greasy" moiety in an attempt to enhance the passage of the
compound through a hydrophobic membrane, such as a cell wall.
[0419] Although the pharmacological properties of the compounds of
the invention (Formulas I and II) vary with structural change, in
general, activity possessed by compounds of Formulas I and II may
be demonstrated both in vitro as well as in vivo. Particularly, the
pharmacological properties of the compounds of this invention may
be confirmed by a number of pharmacological in vitro assays.
[0420] The following biological assays were used to characterize
the ability of compounds of the invention to regulate the cleavage
of amyloid beta precursor protein, thereby reducing or inhibiting
the production of amyloid beta. Compounds of the invention were
found to modulate BACE activity.
In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy
Transfer) Assay (Enzyme Assay)
[0421] Assay buffer is 0.05 M acetate, pH 4.2, 10% DMSO final, 100
uM genapol (which is a nonionic detergent, below it's Critical
Micelle Concentration). Enzyme (0.2 nM) is pre-incubated for one
hour with inhibitors added in 1 uL of DMSO. Then the assay is
started by the addition of FRET substrate (50 nM) and incubated for
one hour. The FRET assay is terminated with by addition of Tris
buffer, which raises the pH to neutrality, and the fluorescence is
determined. The FRET substrate is a peptide with commercially
available fluorophore and quencher, on opposite sides of the BACE
cleavage site. Proteolytic cleavage of the FRET substrate releases
quenching of fluorescence (excitation 488 nm and emission 425 nm).
Data in the in-vitro BACE FRET enzyme assay for those Examples
tested is provided in Table 1.
BACE Cell-Based Assay (Cell Assay)
[0422] The cell-based assay measures inhibition or reduction of
A.beta.40 in conditioned medium of test compound treated cells
expressing amyloid precursor protein.
[0423] Cells stably expressing Amyloid Precursor Protein (APP) were
plated at a density of 40K cells/well in 96 well plates (Costar).
The cells were cultivated for 24 hours at 37.degree. C. and 5%
CO.sub.2 in DMEM supplemented with 10% FBS. The test compounds were
then added to cells in 10-point dose response concentrations with
the starting concentration being either 100 .mu.M or 10 .mu.M. The
compounds were diluted from stock solutions in DMSO and the final
DMSO concentration of the test compounds on cells was 0.1%. After
24 h of incubation with the test compounds the supernatant.
conditioned media was collected and the A.beta. 40 levels were
determined using a sandwich ELISA. The IC.sub.50 of the compound
was calculated from the percent of control or percent inhibition of
A.beta. 40 as a function of the concentration of the test
compound.
[0424] The sandwich ELISA to detect A.beta. 40 was performed in 96
well microtiter plates, which were pre-treated with goat
anti-rabbit IgG (Pierce). The capture and detecting antibody pair
that were used to detect A.beta. 40 from cell supernatants were
affinity purified pAb40 (Biosource) and biotinylated 6E10 (Signet
Labs Inc.), respectively. The optimal concentration for the pAb40
antibody was 3 .mu.g/ml in Superblock/TBS (Pierce) that was
supplemented with 0.05% Tween 20 (Sigma). Optimal concentration for
the detection antibody 6E10-biotinylated was 0.5 .mu.g/ml in
Superblock/TBS (Pierce) that had been supplemented with 2% normal
goat serum and 2% normal mouse serum.
[0425] Cellular supernatants were incubated with the capture
antibody for 3 h at 4.degree. C., followed by 3 wash steps in
TBS-tween (0.05%). The detecting antibody incubation was for 2 h at
4.degree. C., again followed by the wash steps as described
previously. The final readout of the ELISA is Time-Resolved
Fluorescence (counts per minute) using Delfia reagents
Streptavidin-Europium and Enhancement solutions (Perkin Elmer) and
the Victor 2 multilabel counter (Perkin Elmer).
[0426] Data in the in-vitro BACE cell enzyme assay for those
Examples tested is provided in Table 1.
Indications
[0427] Accordingly, compounds of the invention are useful for, but
not limited to, the prevention or treatment of beta-secretase
related diseases, including Alzheimer's disease. The compounds of
the invention have the ability to modulate the formation of amyloid
beta, and reduce the formation and deposition of plaque on the
brain. In one embodiment of the invention, there is provided a
method of treating a disorder related to a beta-secretase enzyme in
a subject, the method comprising administering to the subject an
effective dosage amount of a compound of Formulas I or II. In
another embodiment, there is provided a method of reducing
production of amyloid beta, and of reducing plaque formation. In
yet another embodiment, the invention provides a method of treating
Alzheimer's disease.
[0428] Accordingly, the compounds of the invention would be useful
in therapy as CNS agents in treating neurological disorders and
related conditions.
[0429] Besides being useful for human treatment, these compounds
are useful for veterinary treatment of companion animals, exotic
animals and farm animals, including mammals, rodents, and the like.
For example, animals including horses, dogs, and cats may be
treated with compounds provided by the invention.
Formulations and Method of Use
[0430] Treatment of diseases and disorders herein is intended to
also include therapeutic administration of a compound of the
invention, or a pharmaceutical salt thereof, or a pharmaceutical
composition of either to a subject (i.e., an animal, preferably a
mammal, most preferably a human) which may be in need of
preventative treatment, such as, for example, for pain,
inflammation and the like. Treatment also encompasses prophylactic
administration of a compound of the invention, or a pharmaceutical
salt thereof, or a pharmaceutical composition of either to a
subject (i.e., an animal, preferably a mammal, most preferably a
human). Generally, the subject is initially diagnosed by a licensed
physician and/or authorized medical practitioner, and a regimen for
prophylactic and/or therapeutic treatment via administration of the
compound(s) or compositions of the invention is suggested,
recommended or prescribed.
[0431] The amount of compound(s) which is/are administered and the
dosage regimen for treating neurological disorders and
beta-secretase mediated diseases with the compounds and/or
compositions of this invention depends on a variety of factors,
including the age, weight, sex and medical condition of the
subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about
0.01 to 500 mg/kg, advantageously between about 0.01 and about 50
mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even
more advantageously between about 0.1 and about 10 mg/kg body
weight may be appropriate, and should be useful for all methods of
use disclosed herein. The daily dose can be administered in one to
four doses per day.
[0432] While it may be possible to administer a compound of the
invention alone, in the methods described, the compound
administered normally will be present as an active ingredient in a
pharmaceutical composition. Thus, in another embodiment of the
invention, there is provided a pharmaceutical composition
comprising a compound of this invention in combination with a
pharmaceutically acceptable carrier, which includes diluents,
excipients, adjuvants and the like (collectively referred to herein
as "carrier" materials) as described herein, and, if desired, other
active ingredients. A pharmaceutical composition of the invention
may comprise an effective amount of a compound of the invention or
an effective dosage amount of a compound of the invention. An
effective dosage amount of a compound of the invention includes an
amount less than, equal to or greater than an effective amount of
the compound. For example, a pharmaceutical composition in which
two or more unit dosages, such as in tablets, capsules and the
like, are required to administer an effective amount of the
compound, or alternatively, a multi-dose pharmaceutical
composition, such as powders, liquids and the like, in which an
effective amount of the compound is administered by administering a
portion of the composition. Alternatively, a pharmaceutical
composition in which two or more unit dosages, such as in tablets,
capsules and the like, are required to administer an effective
amount of the compound may be administered in less than an
effective amount for one or more periods of time, for example to
ascertain the effective dose for an individual subject, to
desensitize an individual subject to potential side effects, to
permit effective dosing readjustment or depletion of one or more
other therapeutics administered to an individual subject, and/or
the like.
[0433] The compound(s) of the present invention may be administered
by any suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended. The compounds and compositions of the
present invention may, for example, be administered orally,
mucosally, topically, rectally, pulmonarily such as by inhalation
spray, or parentally including intravascularly, intravenously,
intraperitoneally, subcutaneously, intramuscularly intrastemally
and infusion techniques, in dosage unit formulations containing
conventional pharmaceutically acceptable carriers, adjuvants, and
vehicles.
[0434] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
For example, these may contain an amount of active ingredient from
about 1 to 2000 mg, advantageously from about 1 to 500 mg, and
typically from about 5 to 150 mg. A suitable daily dose for a human
or other mammal may vary widely depending on the condition of the
patient and other factors, but, once again, can be determined using
routine methods and practices.
[0435] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants or
"excipients" appropriate to the indicated route of administration.
If orally administered on a per dose basis, the compounds may be
admixed with lactose, sucrose, starch powder, cellulose esters of
alkanoic acids, cellulose alkyl esters, talc, stearic acid,
magnesium stearate, magnesium oxide, sodium and calcium salts of
phosphoric and sulfuric acids, gelatin, acacia gum, sodium
alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to form
the final formulation. For example, the active compound(s) and
excipient(s) may be tableted or encapsulated by known and accepted
methods for convenient administration. Examples of suitable
formulations include, without limitation, pills, tablets, soft and
hard-shell gel capsules, troches, orally-dissolvable forms and
delayed or controlled-release formulations thereof. Particularly,
capsule or tablet formulations may contain one or more
controlled-release agents, such as hydroxypropylmethyl cellulose,
as a dispersion with the active compound(s).
[0436] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered
by injection as a composition with suitable carriers including
saline, dextrose, or water, or with cyclodextrin (ie. Captisol),
cosolvent solubilization (ie. propylene glycol) or micellar
solubilization (ie. Tween 80).
[0437] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0438] The active ingredient may also be administered by injection
as a composition with suitable carriers including saline, dextrose,
or water. The daily parenteral dosage regimen will be from about
0.1 to about 30 mg/kg of total body weight, and preferably from
about 0.1 to about 10 mg/kg.
[0439] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[0440] The pharmaceutical compositions may be subjected to
conventional pharmaceutical operations such as sterilization and/or
may contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and
pills can additionally be prepared with enteric coatings. Such
compositions may also comprise adjuvants, such as wetting,
sweetening, flavoring, and perfuming agents.
[0441] Accordingly, in yet another embodiment of the present
invention, there is provided a method of manufacturing a
medicament, the method comprising combining an amount of a compound
according to Formulas I or II with a pharmaceutically acceptable
carrier to manufacture the medicament.
[0442] In yet another embodiment, the invention provides a method
of manufacturing a medicament for the treatment of Alzheimer's
disease, the method comprising combining an amount of a compound
according to Formulas I or II with a pharmaceutically acceptable
carrier to manufacture the medicament.
Combinations
[0443] While the compounds of the invention can be dosed or
administered as the sole active pharmaceutical agent, they can also
be used in combination with one or more compounds of the invention
or in conjunction with other agents. When administered as a
combination, the therapeutic agents can be formulated as separate
compositions that are administered simultaneously or sequentially
at different times, or the therapeutic agents can be given as a
single composition.
[0444] The phrase "co-therapy" (or "combination-therapy"), in
defining use of a compound of the present invention and another
pharmaceutical agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[0445] Specifically, the administration of compounds of the present
invention may be in conjunction with additional therapies known to
those skilled in the art in the prevention or treatment of
beta-secretase, gamma-secretase and/or other reagents known in
influence the formation and/or deposition of amyloid beta,
otherwise responsible for the formation of plaque on the brain.
[0446] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the accepted dosage
ranges. Compounds of Formulas I and II may also be administered
sequentially with known anti-inflammatory agents when a combination
formulation is inappropriate. The invention is not limited in the
sequence of administration; compounds of the invention may be
administered either prior to, simultaneous with or after
administration of the known anti-inflammatory agent.
[0447] The foregoing description is merely illustrative of the
invention and is not intended to limit the invention to the
disclosed compounds, compositions and methods. Variations and
changes, which are obvious to one skilled in the art, are intended
to be within the scope and nature of the invention, as defined in
the appended claims. From the foregoing description, one skilled in
the art can easily ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions. All patents and other
publications recited herein are hereby incorporated by reference in
their entireties.
* * * * *